{ "$schema_version": "5.3", "review_mode": "fresh", "claim_restatement": { "index_wording": "Cancer Stem Cell Hypothesis", "entry_form": "phenomenon", "gradeable_restatement": "Discrete self-renewing cancer stem-cell populations organized in stable hierarchies are necessary for tumour maintenance and post-treatment relapse across human cancers.", "restatement_required": true, "split_into": [], "parent_claim": null, "scope_qualifiers": [ { "qualifier": "Tumour histology, anatomical site, genotype, treatment and observation window, defined before the outcome", "determinable_before_outcome": true, "determined_from": "Enrollment and experimental design, before results; no responder-defined scope.", "action": "retained" } ] }, "hypothesis": { "name": "Cancer Stem Cell Hypothesis", "central_claim": "Discrete self-renewing cancer stem-cell populations organized in stable hierarchies are necessary for tumour maintenance and post-treatment relapse across human cancers.", "proposed_mechanism": "Discrete self-renewing cancer stem-cell populations organized in stable hierarchies are necessary for tumour maintenance and post-treatment relapse across human cancers.", "claimed_scope": "Discrete self-renewing cancer stem-cell populations organized in stable hierarchies are necessary for tumour maintenance and post-treatment relapse across human cancers.", "claimed_level": [ "maintenance", "relapse", "cross-cancer necessity" ], "is_conjunctive": true, "conjunctive_note": "The registered gate is cross-cancer generalization SC5. Stable hierarchy and necessary maintenance/relapse are separate; strong endogenous context-specific results do not establish the universal fixed-population model." }, "rubric_routing": { "primary_rubric": "02-cancer-biology.md", "secondary_rubrics": [], "index_notes_applied": [ "The registered gate is cross-cancer generalization SC5. Stable hierarchy and necessary maintenance/relapse are separate; strong endogenous context-specific results do not establish the universal fixed-population model." ], "rubric_fit_note": "Exact archived v5.3 framework. Any stale index empirical framing is rechecked against primary results." }, "subclaim_matrix": { "subclaims": [ { "id": "SC1", "statement": "Hierarchical organization with functionally distinct stem-like cells exists.", "subclaim_type": "existence", "scope": "prespecified tumour histologies and endogenous experimental contexts", "claimed_scope": "prespecified tumour histologies and endogenous experimental contexts", "governing_rubric": "02-cancer-biology.md", "key_evidence_anchor": "Endogenous lineage tracing", "hsef_level": "Ζ", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Endogenous skin, intestinal and glioma tracing, supported by human-origin functional assays, independently establishes functional hierarchy/stem-like contribution in defined settings. It does not establish permanent marker identity in every cancer." }, { "id": "SC2", "statement": "A discrete CSC population is necessary for tumour maintenance.", "subclaim_type": "necessity", "scope": "defined native or patient-derived tumours", "claimed_scope": "defined native or patient-derived tumours", "governing_rubric": "02-cancer-biology.md", "key_evidence_anchor": "Selective endogenous ablation and rescue", "hsef_level": "Ε", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Precise Sox2, Prom1 and HPCS perturbations impair growth in defined native models. Lgr5-negative CRC maintenance and context-specific niche dependence delimit the necessity claim; CSC-like function can be required without an irreplaceable fixed population." }, { "id": "SC3", "statement": "CSCs are necessary for relapse after treatment.", "subclaim_type": "necessity", "scope": "defined treated tumours and relapse horizons", "claimed_scope": "defined treated tumours and relapse horizons", "governing_rubric": "02-cancer-biology.md", "key_evidence_anchor": "Pretherapy clone/state tracking and ablation", "hsef_level": "Ε", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Glioma, BCC, p57 and residual CRC tests demonstrate treatment/stage-dependent relapse dependencies. EMP1 ablation before surgery and after seeding differ; selective Lgr5 depletion can fail to prevent CRC relapse. Clinical universal relapse prevention is not demonstrated." }, { "id": "SC4", "statement": "The hierarchy is stable rather than a reversible cell state.", "subclaim_type": "mechanism", "scope": "native tumours under baseline and treatment conditions", "claimed_scope": "native tumours under baseline and treatment conditions", "governing_rubric": "02-cancer-biology.md", "key_evidence_anchor": "Bidirectional fate mapping", "hsef_level": "Γ", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Permanent one-way membership remains a plausible local description, but mammary intravital tracing, AML differentiation reversal, CRC regrowth and HPCS re-entry directly contradict its broad stability prediction. The level records the unestablished general mechanism, not endorsement of stability." }, { "id": "SC5", "statement": "A fixed discrete CSC hierarchy is necessary across human cancers.", "subclaim_type": "primacy", "scope": "human haematological and solid cancers", "claimed_scope": "human haematological and solid cancers", "governing_rubric": "02-cancer-biology.md", "key_evidence_anchor": "Across-histology causal dependency with plasticity tests", "hsef_level": "Γ", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "The preregistered cross-human-cancer fixed-population gate is not crossed. Strong causal successes in defined models do not establish the conjunction of stable hierarchy, irreplaceable membership and necessary maintenance/relapse across human haematological and solid cancers." } ], "aggregation_rule": "scope-matched", "aggregation_preregistered": true, "aggregation_rationale": "The registered gate is cross-cancer generalization SC5. Stable hierarchy and necessary maintenance/relapse are separate; strong endogenous context-specific results do not establish the universal fixed-population model.", "primary_subclaim_id": "SC5", "aggregation_derivation": "Γ for the exact registered broad fixed-hierarchy claim. The cancer rubric explicitly permits Ε for context-specific CSC validity; that threshold is awarded to SC2 and SC3 rather than silently replacing SC5 with a weaker functional-stemness statement. Across-context causal studies are credited as a convergent set, but their results include genuine population replacement, stage-specific dispensability and alternative lineage routes. They therefore do not cross the fixed cross-human necessity gate. Scope-matched and primary-subclaim aggregation both return Γ; weakest-link also returns Γ. Narrow existence is Ζ, and defined maintenance/relapse dependencies are Ε.", "aggregation_alternatives": { "weakest_link_would_return": "Γ", "primary_subclaim_would_return": "Γ", "scope_matched_would_return": "Γ", "note": "Separate narrow successes do not replace the preregistered gate." }, "index_rule_deviation": "" }, "competing_models": { "models_evaluated": [ { "rank_in_tournament": 1, "model_id": "M4", "is_nominal": false, "name": "Context-dependent hybrid hierarchy/plasticity", "core_claim": "Functional hierarchies coexist with changing membership and genetic/niche constraints.", "explains_what_nominal_does_not": "Functional hierarchies coexist with changing membership and genetic/niche constraints.", "strongest_supporting_evidence": [ "Native tracing/ablation and human CRC regrowth jointly support important stem states with replacement; PMID22854781, PMID28355176 and PMID41565826." ], "strongest_contradictory_evidence": [ "A hybrid is broad and requires prospective transition/dependency predictions to avoid explaining every possible outcome." ], "hsef_level_for_this_model": "Ζ", "rationale": "Native tracing/ablation and human CRC regrowth jointly support important stem states with replacement; PMID22854781, PMID28355176 and PMID41565826. A hybrid is broad and requires prospective transition/dependency predictions to avoid explaining every possible outcome." }, { "rank_in_tournament": 2, "model_id": "M2", "is_nominal": false, "name": "Reversible state plasticity", "core_claim": "Tumour cells can enter or leave self-renewing/therapy-resistant states.", "explains_what_nominal_does_not": "Tumour cells can enter or leave self-renewing/therapy-resistant states.", "strongest_supporting_evidence": [ "Mammary intravital tracing, AML reversal, CRC negative-to-positive recovery and orthotopic HPCS re-entry exclude permanent one-way membership in these settings." ], "strongest_contradictory_evidence": [ "Not every tumour cell is equipotent and BCC shows limited short-term recovery; plastic capacity is not sufficient to explain every relapse." ], "hsef_level_for_this_model": "Ζ", "rationale": "Mammary intravital tracing, AML reversal, CRC negative-to-positive recovery and orthotopic HPCS re-entry exclude permanent one-way membership in these settings. Not every tumour cell is equipotent and BCC shows limited short-term recovery; plastic capacity is not sufficient to explain every relapse." }, { "rank_in_tournament": 3, "model_id": "M5", "is_nominal": false, "name": "Microenvironment-dependent stemness", "core_claim": "Location and stromal or metabolic signals determine functional stemness.", "explains_what_nominal_does_not": "Location and stromal or metabolic signals determine functional stemness.", "strongest_supporting_evidence": [ "Marker-free pancreatic tracing, CRC edge clones and lactate/COL17A1 perturbations support niche-dependent behaviour." ], "strongest_contradictory_evidence": [ "CRC metastasis and genetic driver history also supply cell-intrinsic mechanisms; one niche model does not explain all cancer classes." ], "hsef_level_for_this_model": "Ε", "rationale": "Marker-free pancreatic tracing, CRC edge clones and lactate/COL17A1 perturbations support niche-dependent behaviour. CRC metastasis and genetic driver history also supply cell-intrinsic mechanisms; one niche model does not explain all cancer classes." }, { "rank_in_tournament": 4, "model_id": "M3", "is_nominal": false, "name": "Clonal evolution", "core_claim": "Genetic subclones selected by therapy generate propagation and resistance.", "explains_what_nominal_does_not": "Genetic subclones selected by therapy generate propagation and resistance.", "strongest_supporting_evidence": [ "Human AML paired sampling and single-cell genotypes, and pancreatic replica clones, establish selected resistant lineages." ], "strongest_contradictory_evidence": [ "Genetically stable CRC clones show functional variability and multiple states can interconvert; mutation alone does not explain membership." ], "hsef_level_for_this_model": "Ε", "rationale": "Human AML paired sampling and single-cell genotypes, and pancreatic replica clones, establish selected resistant lineages. Genetically stable CRC clones show functional variability and multiple states can interconvert; mutation alone does not explain membership." }, { "rank_in_tournament": 5, "model_id": "M1", "is_nominal": true, "name": "Fixed CSC hierarchy", "core_claim": "A discrete self-renewing apex has stable membership and is irreplaceable across human cancers.", "explains_what_nominal_does_not": "A discrete self-renewing apex has stable membership and is irreplaceable across human cancers.", "strongest_supporting_evidence": [ "Historical AML/breast/brain transplantation and native Sox2/glioma/BCC dependencies provide the strongest local case." ], "strongest_contradictory_evidence": [ "Permissive melanoma assays, mature AML reversal, Lgr5-negative CRC maintenance, EMP1 timing and HPCS replenishment contradict universal fixed membership." ], "hsef_level_for_this_model": "Γ", "rationale": "Historical AML/breast/brain transplantation and native Sox2/glioma/BCC dependencies provide the strongest local case. Permissive melanoma assays, mature AML reversal, Lgr5-negative CRC maintenance, EMP1 timing and HPCS replenishment contradict universal fixed membership." } ], "tournament_summary": "Descriptive comparison; does not modify the nominal score. A prospective native lineage study coupling clone ancestry, reversible state measurement, selective ablation and restoration under identical treatment could separate a plastic functional hierarchy from pure state-equilibrium explanations. Neither rival is awarded universal necessity.", "study_separating_rank1_from_rank2": "A prospective native lineage study coupling clone ancestry, reversible state measurement, selective ablation and restoration under identical treatment could separate a plastic functional hierarchy from pure state-equilibrium explanations. Neither rival is awarded universal necessity.", "nominal_wins_only_by_funding_artifact": false, "level_unchanged_by_tournament": true }, "evidence_inventory": [ { "n": 1, "pmid": "7509044", "title": "A cell initiating human acute myeloid leukaemia after transplantation into SCID mice.", "citation": "Lapidot T, Sirard C, Vormoor J et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature. 1994.", "doi": "10.1038/367645a0", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/7509044/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/7509044/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID7509044", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "human experimental", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Marker-fractionated human AML cells initiated disseminated leukemia in cytokine-treated SCID hosts, defining transplantation-enriched initiating activity.", "what_it_does_not_show": "Engraftment selection does not establish an immutable endogenous hierarchy or necessity for maintenance and relapse in patients.", "confounders_present": [ "Engraftment selection does not establish an immutable endogenous hierarchy or necessity for maintenance and relapse in patients." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [ "Human-to-immunodeficient-mouse engraftment selection; cytokine/host permissiveness." ] }, { "n": 2, "pmid": "9212098", "title": "Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell.", "citation": "Bonnet D, Dick JE et al. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nature medicine. 1997.", "doi": "10.1038/nm0797-730", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/9212098/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/9212098/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID9212098", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "human experimental", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Primitive CD34-high CD38-negative fractions from tested AML subtypes self-renewed and generated differentiated leukemic blasts in NOD/SCID mice.", "what_it_does_not_show": "Assay-defined exclusivity need not persist with different host permissiveness or show the original patient's tumour maintenance mechanism.", "confounders_present": [ "Assay-defined exclusivity need not persist with different host permissiveness or show the original patient's tumour maintenance mechanism." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [ "Human-to-immunodeficient-mouse engraftment selection; not independent of host selection as a failure class." ] }, { "n": 3, "pmid": "12629218", "title": "Prospective identification of tumorigenic breast cancer cells.", "citation": "Al-Hajj M, Wicha MS, Benito-Hernandez A et al. Prospective identification of tumorigenic breast cancer cells. Proceedings of the National Academy of Sciences of the United States of America. 2003.", "doi": "10.1073/pnas.0530291100", "pmcid": "PMC153034", "url": "https://pubmed.ncbi.nlm.nih.gov/12629218/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/12629218/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID not supplied" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID12629218", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "human experimental", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Prospectively isolated CD44-positive CD24-low breast tumour cells showed enriched serial tumour formation and regenerated heterogeneity in immunocompromised mice.", "what_it_does_not_show": "Selected xenograft initiation in a small patient series is not universal fixed-hierarchy necessity; linked erratum details were not resolved.", "confounders_present": [ "Selected xenograft initiation in a small patient series is not universal fixed-hierarchy necessity; linked erratum details were not resolved." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [ "Marker sorting and immunocompromised-host initiation shared with other early solid-tumour assays." ] }, { "n": 4, "pmid": "15549107", "title": "Identification of human brain tumour initiating cells.", "citation": "Singh SK, Hawkins C, Clarke ID et al. Identification of human brain tumour initiating cells. Nature. 2004.", "doi": "10.1038/nature03128", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/15549107/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/15549107/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID15549107", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "human experimental", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "CD133-positive human brain tumour fractions generated serially transplantable phenocopies at lower inocula than the tested negative fractions.", "what_it_does_not_show": "CD133 enrichment in this host assay does not establish permanent marker exclusivity, endogenous maintenance necessity or relapse prevention.", "confounders_present": [ "CD133 enrichment in this host assay does not establish permanent marker exclusivity, endogenous maintenance necessity or relapse prevention." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [ "Marker sorting and immunocompromised-host initiation shared with other early solid-tumour assays." ] }, { "n": 5, "pmid": "18765800", "title": "Single-cell cloning of colon cancer stem cells reveals a multi-lineage differentiation capacity.", "citation": "Vermeulen L, Todaro M, de Sousa Mello F et al. Single-cell cloning of colon cancer stem cells reveals a multi-lineage differentiation capacity. Proceedings of the National Academy of Sciences of the United States of America. 2008.", "doi": "10.1073/pnas.0805706105", "pmcid": "PMC2533206", "url": "https://pubmed.ncbi.nlm.nih.gov/18765800/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/18765800/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID18765800", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human experimental", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Single colon cancer cells self-renewed and generated differentiated tumour progeny after culture and xenotransplantation; PI3K signalling affected lineage decisions.", "what_it_does_not_show": "Clonal multilineage potential is compatible with plastic hierarchies and does not prove an irreplaceable fixed population in patients.", "confounders_present": [ "Clonal multilineage potential is compatible with plastic hierarchies and does not prove an irreplaceable fixed population in patients." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 6, "pmid": "19052619", "title": "Efficient tumour formation by single human melanoma cells.", "citation": "Quintana E, Shackleton M, Sabel MS et al. Efficient tumour formation by single human melanoma cells. Nature. 2008.", "doi": "10.1038/nature07567", "pmcid": "PMC2597380", "url": "https://pubmed.ncbi.nlm.nih.gov/19052619/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/19052619/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID19052619", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC4", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "human experimental", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "More permissive host conditions detected tumour formation from many unselected human melanoma cells, including single-cell inocula.", "what_it_does_not_show": "High transplantation competence challenges rarity and assay exclusivity but alone does not quantify endogenous fate or refute all functional hierarchies.", "confounders_present": [ "High transplantation competence challenges rarity and assay exclusivity but alone does not quantify endogenous fate or refute all functional hierarchies." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [ "Permissive NSG transplantation platform also used in PMID21075313." ] }, { "n": 7, "pmid": "20048081", "title": "Characterization of melanoma cells capable of propagating tumors from a single cell.", "citation": "Held MA, Curley DP, Dankort D et al. Characterization of melanoma cells capable of propagating tumors from a single cell. Cancer research. 2010.", "doi": "10.1158/0008-5472.CAN-09-2153", "pmcid": "PMC4026296", "url": "https://pubmed.ncbi.nlm.nih.gov/20048081/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/20048081/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID20048081", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC4", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal experimental", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "Single-cell melanoma transplants revealed multiple propagating phenotypes with different capacities to reconstruct heterogeneity and resist chemotherapy.", "what_it_does_not_show": "Transplanted mouse tumour populations do not establish patient recurrence mechanisms; self-renewal need not require multilineage differentiation.", "confounders_present": [ "Transplanted mouse tumour populations do not establish patient recurrence mechanisms; self-renewal need not require multilineage differentiation." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 8, "pmid": "18485877", "title": "The epithelial-mesenchymal transition generates cells with properties of stem cells.", "citation": "Mani SA, Guo W, Liao MJ et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell. 2008.", "doi": "10.1016/j.cell.2008.03.027", "pmcid": "PMC2728032", "url": "https://pubmed.ncbi.nlm.nih.gov/18485877/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/18485877/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID18485877", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human experimental", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "Inducing EMT in mammary epithelial systems increased stem-associated properties and tumour-forming activity after transformation.", "what_it_does_not_show": "Induced EMT and sphere readouts do not measure natural bidirectional transitions or establish universal therapy-resistant CSC identity.", "confounders_present": [ "Induced EMT and sphere readouts do not measure natural bidirectional transitions or establish universal therapy-resistant CSC identity." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 9, "pmid": "21498687", "title": "Normal and neoplastic nonstem cells can spontaneously convert to a stem-like state.", "citation": "Chaffer CL, Brueckmann I, Scheel C et al. Normal and neoplastic nonstem cells can spontaneously convert to a stem-like state. Proceedings of the National Academy of Sciences of the United States of America. 2011.", "doi": "10.1073/pnas.1102454108", "pmcid": "PMC3093533", "url": "https://pubmed.ncbi.nlm.nih.gov/21498687/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/21498687/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID21498687", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human experimental", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "Purified mammary non-stem populations spontaneously generated stem-like cells, with enhanced conversion after transformation in vitro and in vivo.", "what_it_does_not_show": "Selected mammary systems do not establish transition rates across all tumours; spontaneous conversion undermines a permanently one-way hierarchy.", "confounders_present": [ "Selected mammary systems do not establish transition rates across all tumours; spontaneous conversion undermines a permanently one-way hierarchy." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 10, "pmid": "21854987", "title": "Stochastic state transitions give rise to phenotypic equilibrium in populations of cancer cells.", "citation": "Gupta PB, Fillmore CM, Jiang G et al. Stochastic state transitions give rise to phenotypic equilibrium in populations of cancer cells. Cell. 2011.", "doi": "10.1016/j.cell.2011.07.026", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/21854987/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/21854987/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID not supplied", "ErratumIn: PMID not supplied" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID21854987", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human experimental", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "Sorted breast cancer cell-line states returned toward equilibrium proportions, consistent with stochastic transitions and de novo stem-like states.", "what_it_does_not_show": "A Markov fit and cultured state recovery do not uniquely identify endogenous patient fate dynamics; two linked errata remain unresolved.", "confounders_present": [ "A Markov fit and cultured state recovery do not uniquely identify endogenous patient fate dynamics; two linked errata remain unresolved." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 11, "pmid": "21873988", "title": "Stem cell gene expression programs influence clinical outcome in human leukemia.", "citation": "Eppert K, Takenaka K, Lechman ER et al. Stem cell gene expression programs influence clinical outcome in human leukemia. Nature medicine. 2011.", "doi": "10.1038/nm.2415", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/21873988/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/21873988/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID21873988", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "human experimental", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Functionally xenograft-validated human AML stemness programs predicted patient survival, bridging transplantation activity and clinical association.", "what_it_does_not_show": "Prognostic prediction is not selective LSC eradication or proof that a fixed population is necessary for relapse.", "confounders_present": [ "Prognostic prediction is not selective LSC eradication or proof that a fixed population is necessary for relapse." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 12, "pmid": "24522528", "title": "Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia.", "citation": "Shlush LI, Zandi S, Mitchell A et al. Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia. Nature. 2014.", "doi": "10.1038/nature13038", "pmcid": "PMC4991939", "url": "https://pubmed.ncbi.nlm.nih.gov/24522528/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/24522528/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID not supplied" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID24522528", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human experimental", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "DNMT3A-mutant pre-leukemic HSCs lacked later NPM1 lesions, repopulated multilineage xenografts and persisted in remission samples.", "what_it_does_not_show": "A pre-leukemic reservoir is not identical to the overt AML-maintaining population; presence after chemotherapy does not prove inevitable relapse.", "confounders_present": [ "A pre-leukemic reservoir is not identical to the overt AML-maintaining population; presence after chemotherapy does not prove inevitable relapse." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 13, "pmid": "30827681", "title": "Single-Cell RNA-Seq Reveals AML Hierarchies Relevant to Disease Progression and Immunity.", "citation": "van Galen P, Hovestadt V, Wadsworth Ii MH et al. Single-Cell RNA-Seq Reveals AML Hierarchies Relevant to Disease Progression and Immunity. Cell. 2019.", "doi": "10.1016/j.cell.2019.01.031", "pmcid": "PMC6515904", "url": "https://pubmed.ncbi.nlm.nih.gov/30827681/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30827681/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID30827681", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC4", "SC5" ], "favors_models": [], "evidence_class": "Weak", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Single-cell genotyping and transcriptional profiling mapped variable malignant differentiation spectra across AML patients and subclones.", "what_it_does_not_show": "Expression-defined primitive states and prognosis do not by themselves establish lineage direction, necessity or a stable universal hierarchy.", "confounders_present": [ "Expression-defined primitive states and prognosis do not by themselves establish lineage direction, necessity or a stable universal hierarchy." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 14, "pmid": "28658204", "title": "Tracing the origins of relapse in acute myeloid leukaemia to stem cells.", "citation": "Shlush LI, Mitchell A, Heisler L et al. Tracing the origins of relapse in acute myeloid leukaemia to stem cells. Nature. 2017.", "doi": "10.1038/nature22993", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/28658204/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/28658204/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID28658204", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC4", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "human experimental", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Paired diagnosis/relapse genetics and xenografts traced resistant origins to either rare primitive LSCs or larger committed-phenotype subclones retaining stemness signatures.", "what_it_does_not_show": "The two relapse patterns support functional stemness while contradicting a universal rare primitive phenotype; no randomized selective patient LSC ablation was tested.", "confounders_present": [ "The two relapse patterns support functional stemness while contradicting a universal rare primitive phenotype; no randomized selective patient LSC ablation was tested." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 15, "pmid": "23239622", "title": "Variable clonal repopulation dynamics influence chemotherapy response in colorectal cancer.", "citation": "Kreso A, O'Brien CA, van Galen P et al. Variable clonal repopulation dynamics influence chemotherapy response in colorectal cancer. Science (New York, N.Y.). 2013.", "doi": "10.1126/science.1227670", "pmcid": "PMC9747244", "url": "https://pubmed.ncbi.nlm.nih.gov/23239622/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/23239622/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID23239622", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human experimental", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "Lentiviral tracking within genetically stable colorectal clones revealed variable propagation and chemotherapy-selected minor or dormant lineages.", "what_it_does_not_show": "Serial xenografts select engraftment-capable cells and do not distinguish every source of state variability in untreated patients.", "confounders_present": [ "Serial xenografts select engraftment-capable cells and do not distinguish every source of state variability in untreated patients." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 16, "pmid": "22855427", "title": "Lineage tracing reveals Lgr5+ stem cell activity in mouse intestinal adenomas.", "citation": "Schepers AG, Snippert HJ, Stange DE et al. Lineage tracing reveals Lgr5+ stem cell activity in mouse intestinal adenomas. Science (New York, N.Y.). 2012.", "doi": "10.1126/science.1224676", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/22855427/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/22855427/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID22855427", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "animal experimental", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Endogenous multicolour lineage retracing showed Lgr5-positive adenoma cells self-renewing and producing the other adenoma cell types.", "what_it_does_not_show": "A lineage contribution in mouse precursor adenomas is not necessity, patient carcinoma relapse, or proof that negative cells cannot regenerate stemness.", "confounders_present": [ "A lineage contribution in mouse precursor adenomas is not necessity, patient carcinoma relapse, or proof that negative cells cannot regenerate stemness." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 17, "pmid": "22854777", "title": "Defining the mode of tumour growth by clonal analysis.", "citation": "Driessens G, Beck B, Caauwe A et al. Defining the mode of tumour growth by clonal analysis. Nature. 2012.", "doi": "10.1038/nature11344", "pmcid": "PMC5553110", "url": "https://pubmed.ncbi.nlm.nih.gov/22854777/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/22854777/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID22854777", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "animal experimental", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Genetic clonal tracing in native skin tumours distinguished persistent stem-like and transient compartments in papillomas, with different dynamics in invasive carcinoma.", "what_it_does_not_show": "Contribution and stage-dependent clonal behaviour do not prove universal rare-CSC necessity or an invariant hierarchy through progression.", "confounders_present": [ "Contribution and stage-dependent clonal behaviour do not prove universal rare-CSC necessity or an invariant hierarchy through progression." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 18, "pmid": "22854781", "title": "A restricted cell population propagates glioblastoma growth after chemotherapy.", "citation": "Chen J, Li Y, Yu TS et al. A restricted cell population propagates glioblastoma growth after chemotherapy. Nature. 2012.", "doi": "10.1038/nature11287", "pmcid": "PMC3427400", "url": "https://pubmed.ncbi.nlm.nih.gov/22854781/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/22854781/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID22854781", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "animal experimental", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Pulse-chase and transgene-directed ablation identified an endogenous glioma subset sustaining regrowth after temozolomide; chronic ganciclovir arrested growth and combination treatment impeded development.", "what_it_does_not_show": "The engineered glioma and nestin-TK targeting define a context-specific dependency, not universal patient CSC identity or selective clinical relapse prevention.", "confounders_present": [ "The engineered glioma and nestin-TK targeting define a context-specific dependency, not universal patient CSC identity or selective clinical relapse prevention." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 19, "pmid": "28355176", "title": "Visualization and targeting of LGR5+ human colon cancer stem cells.", "citation": "Shimokawa M, Ohta Y, Nishikori S et al. Visualization and targeting of LGR5+ human colon cancer stem cells. Nature. 2017.", "doi": "10.1038/nature22081", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/28355176/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/28355176/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID28355176", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human experimental", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "Human CRC organoid lineage tracing and selective LGR5 ablation caused regression followed by regrowth involving KRT20-lineage conversion into LGR5-positive cells.", "what_it_does_not_show": "Engineered organoid xenografts show a plastic functional hierarchy rather than necessity of a permanently distinct pre-existing CSC population in patients.", "confounders_present": [ "Engineered organoid xenografts show a plastic functional hierarchy rather than necessity of a permanently distinct pre-existing CSC population in patients." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [ "LGR5-engineered organoid tracing and selective ablation; marker-dependent measurement can miss state changes." ] }, { "n": 20, "pmid": "28358093", "title": "A distinct role for Lgr5+ stem cells in primary and metastatic colon cancer.", "citation": "de Sousa e Melo F, Kurtova AV, Harnoss JM et al. A distinct role for Lgr5+ stem cells in primary and metastatic colon cancer. Nature. 2017.", "doi": "10.1038/nature21713", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/28358093/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/28358093/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID28358093", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3", "SC4", "SC5" ], "favors_models": [], "evidence_class": "Strong", "system": "animal experimental", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "Selective Lgr5 ablation restricted primary CRC growth without regression while negative cells replenished the pool; liver metastases showed stronger Lgr5 dependence.", "what_it_does_not_show": "Dependency differs by anatomical stage; primary maintenance despite ablation contradicts universal fixed-population necessity while preserving a metastatic dependency.", "confounders_present": [ "Dependency differs by anatomical stage; primary maintenance despite ablation contradicts universal fixed-population necessity while preserving a metastatic dependency." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [ "Lgr5-dependent CRC tracing/ablation family; source generation route not resolved from accessible body." ] }, { "n": 21, "pmid": "28468934", "title": "A genome editing approach to study cancer stem cells in human tumors.", "citation": "Cortina C, Turon G, Stork D et al. A genome editing approach to study cancer stem cells in human tumors. EMBO molecular medicine. 2017.", "doi": "10.15252/emmm.201707550", "pmcid": "PMC5494503", "url": "https://pubmed.ncbi.nlm.nih.gov/28468934/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/28468934/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID28468934", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human experimental", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Edited patient-derived CRC organoid xenografts showed long-term LGR5-lineage self-renewal and differentiated descendants.", "what_it_does_not_show": "Human-origin material in an engineered mouse host is not intact-patient fate tracing, and lineage contribution alone does not demonstrate necessity.", "confounders_present": [ "Human-origin material in an engineered mouse host is not intact-patient fate tracing, and lineage contribution alone does not demonstrate necessity." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 22, "pmid": "26679053", "title": "Phenotypic differentiation does not affect tumorigenicity of primary human colon cancer initiating cells.", "citation": "Dubash TD, Hoffmann CM, Oppel F et al. Phenotypic differentiation does not affect tumorigenicity of primary human colon cancer initiating cells. Cancer letters. 2016.", "doi": "10.1016/j.canlet.2015.11.037", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/26679053/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26679053/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID26679053", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human experimental", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "CRC cells downregulated initiating-cell markers under differentiating adherent conditions yet retained serial xenograft tumour initiation and clonal contribution.", "what_it_does_not_show": "Culture-induced marker differentiation does not identify every endogenous transition, but marker-defined phenotype was not necessary for transplantation activity.", "confounders_present": [ "Culture-induced marker differentiation does not identify every endogenous transition, but marker-defined phenotype was not necessary for transplantation activity." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 23, "pmid": "32169167", "title": "Plasticity of Lgr5-Negative Cancer Cells Drives Metastasis in Colorectal Cancer.", "citation": "Fumagalli A, Oost KC, Kester L et al. Plasticity of Lgr5-Negative Cancer Cells Drives Metastasis in Colorectal Cancer. Cell stem cell. 2020.", "doi": "10.1016/j.stem.2020.02.008", "pmcid": "PMC7118369", "url": "https://pubmed.ncbi.nlm.nih.gov/32169167/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32169167/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID32169167", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "animal experimental", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "Mouse CRC and human xenograft tracking showed many disseminating Lgr5-negative cells restoring positive stem-like cells; plasticity supported metastatic outgrowth.", "what_it_does_not_show": "Seeding, establishment and outgrowth are distinct phases; a plastic stem state requirement is not a fixed originating cell population requirement.", "confounders_present": [ "Seeding, establishment and outgrowth are distinct phases; a plastic stem state requirement is not a fixed originating cell population requirement." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 24, "pmid": "36352230", "title": "Metastatic recurrence in colorectal cancer arises from residual EMP1+ cells.", "citation": "Cañellas-Socias A, Cortina C, Hernando-Momblona X et al. Metastatic recurrence in colorectal cancer arises from residual EMP1+ cells. Nature. 2022.", "doi": "10.1038/s41586-022-05402-9", "pmcid": "PMC7616986", "url": "https://pubmed.ncbi.nlm.nih.gov/36352230/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36352230/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID36352230", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 5:Relapse by residual EMP1+ cells. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "animal experimental", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "In orthotopic CRC relapse models, pre-resection EMP1-high ablation prevented recurrence in most mice; post-seeding ablation failed, and pre-resection Lgr5 ablation did not prevent recurrence.", "what_it_does_not_show": "Timing and metastatic stage determine dependency; patient signatures were associative, and EMP1 residual states are not an immutable LGR5 apex.", "confounders_present": [ "Timing and metastatic stage determine dependency; patient signatures were associative, and EMP1 residual states are not an immutable LGR5 apex." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [ "Orthotopically transplanted engineered CRC organoid lines; resection and seeding timing are shared determinants." ] }, { "n": 25, "pmid": "35773527", "title": "Mex3a marks drug-tolerant persister colorectal cancer cells that mediate relapse after chemotherapy.", "citation": "Álvarez-Varela A, Novellasdemunt L, Barriga FM et al. Mex3a marks drug-tolerant persister colorectal cancer cells that mediate relapse after chemotherapy. Nature cancer. 2022.", "doi": "10.1038/s43018-022-00402-0", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/35773527/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35773527/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID35773527", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "animal experimental", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Mex3a-lineage persisters expanded after chemotherapy and transiently shifted away from the WNT/stem program; deficient cells differentiated and failed to resist treatment.", "what_it_does_not_show": "A therapy-dependent, niche-adaptive persister state is not an invariant CSC phenotype; clinical selective targeting and durable patient relapse prevention were not tested.", "confounders_present": [ "A therapy-dependent, niche-adaptive persister state is not an invariant CSC phenotype; clinical selective targeting and durable patient relapse prevention were not tested." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 26, "pmid": "35931031", "title": "Dynamic and adaptive cancer stem cell population admixture in colorectal neoplasia.", "citation": "Vasquez EG, Nasreddin N, Valbuena GN et al. Dynamic and adaptive cancer stem cell population admixture in colorectal neoplasia. Cell stem cell. 2022.", "doi": "10.1016/j.stem.2022.07.008", "pmcid": "PMC9592560", "url": "https://pubmed.ncbi.nlm.nih.gov/35931031/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35931031/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID36332574" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID35931031", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal experimental", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "Mouse and human neoplasia showed variable conventional/regenerative stem-state admixture that adapted under acute selective pressure and tracked chemoresistance.", "what_it_does_not_show": "The fitness-landscape interpretation is not a unique proof of transition causation; a linked corrigendum remains part of the access limit.", "confounders_present": [ "The fitness-landscape interpretation is not a unique proof of transition causation; a linked corrigendum remains part of the access limit." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 27, "pmid": "34686335", "title": "Marker-free lineage tracing reveals an environment-instructed clonogenic hierarchy in pancreatic cancer.", "citation": "Lodestijn SC, Miedema DM, Lenos KJ et al. Marker-free lineage tracing reveals an environment-instructed clonogenic hierarchy in pancreatic cancer. Cell reports. 2021.", "doi": "10.1016/j.celrep.2021.109852", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/34686335/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34686335/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID34686335", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC4", "SC5" ], "favors_models": [], "evidence_class": "Strong", "system": "animal experimental", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "Marker-independent in-situ pancreatic clonal tracing found widespread clonogenic potential controlled by fibroblast proximity; stromal Hedgehog inhibition altered growth mode.", "what_it_does_not_show": "Spatially instructed clonogenicity challenges a fixed rare apex, but the perturbation can change multiple stromal functions and does not cover every PDAC subtype.", "confounders_present": [ "Spatially instructed clonogenicity challenges a fixed rare apex, but the perturbation can change multiple stromal functions and does not cover every PDAC subtype." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 28, "pmid": "28526679", "title": "Succession of transiently active tumor-initiating cell clones in human pancreatic cancer xenografts.", "citation": "Ball CR, Oppel F, Ehrenberg KR et al. Succession of transiently active tumor-initiating cell clones in human pancreatic cancer xenografts. EMBO molecular medicine. 2017.", "doi": "10.15252/emmm.201607354", "pmcid": "PMC5494525", "url": "https://pubmed.ncbi.nlm.nih.gov/28526679/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/28526679/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID28526679", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human experimental", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "Serial pancreatic xenografts were maintained by successive transiently active initiating clones with little overlap between generations.", "what_it_does_not_show": "Transplant bottlenecks may contribute to clonal succession; these data challenge fixed continual activity without establishing native patient dynamics.", "confounders_present": [ "Transplant bottlenecks may contribute to clonal succession; these data challenge fixed continual activity without establishing native patient dynamics." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 29, "pmid": "30726735", "title": "Pre-existing Functional Heterogeneity of Tumorigenic Compartment as the Origin of Chemoresistance in Pancreatic Tumors.", "citation": "Seth S, Li CY, Ho IL et al. Pre-existing Functional Heterogeneity of Tumorigenic Compartment as the Origin of Chemoresistance in Pancreatic Tumors. Cell reports. 2019.", "doi": "10.1016/j.celrep.2019.01.048", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/30726735/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30726735/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID30726735", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human experimental", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Clonal replica pancreatic xenografts exposed pre-existing genetic and functional diversity with different gemcitabine responses.", "what_it_does_not_show": "Drug sensitivity and predictive signatures do not show that one stable CSC compartment is necessary for patient relapse.", "confounders_present": [ "Drug sensitivity and predictive signatures do not show that one stable CSC compartment is necessary for patient relapse." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 30, "pmid": "32977829", "title": "A single-cell survey of cellular hierarchy in acute myeloid leukemia.", "citation": "Wu J, Xiao Y, Sun J et al. A single-cell survey of cellular hierarchy in acute myeloid leukemia. Journal of hematology & oncology. 2020.", "doi": "10.1186/s13045-020-00941-y", "pmcid": "PMC7517826", "url": "https://pubmed.ncbi.nlm.nih.gov/32977829/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32977829/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID32977829", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC5" ], "favors_models": [], "evidence_class": "Weak", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Single-cell sequencing of AML marrow resolved progenitor states and associations between ribosomal programs, subtype and remission.", "what_it_does_not_show": "A transcriptomic landscape and proposed attractor do not demonstrate fate direction, selective dependency or population immutability.", "confounders_present": [ "A transcriptomic landscape and proposed attractor do not demonstrate fate direction, selective dependency or population immutability." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 31, "pmid": "37098346", "title": "Clonally resolved single-cell multi-omics identifies routes of cellular differentiation in acute myeloid leukemia.", "citation": "Beneyto-Calabuig S, Merbach AK, Kniffka JA et al. Clonally resolved single-cell multi-omics identifies routes of cellular differentiation in acute myeloid leukemia. Cell stem cell. 2023.", "doi": "10.1016/j.stem.2023.04.001", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/37098346/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37098346/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID37098346", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC4", "SC5" ], "favors_models": [], "evidence_class": "Weak", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "CloneTracer connected genotypes with differentiation routes in AML, separating healthy/pre-leukemic dormant cells from active LSC-like and downstream malignant compartments.", "what_it_does_not_show": "Inferred routes and chemotherapy associations do not constitute selective in-patient stem-cell ablation or prove a universal fixed phenotype.", "confounders_present": [ "Inferred routes and chemotherapy associations do not constitute selective in-patient stem-cell ablation or prove a universal fixed phenotype." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 32, "pmid": "40010350", "title": "Pre-existing stem cell heterogeneity dictates clonal responses to the acquisition of leukemic driver mutations.", "citation": "Singh I, Fernandez-Perez D, Sanchez PS et al. Pre-existing stem cell heterogeneity dictates clonal responses to the acquisition of leukemic driver mutations. Cell stem cell. 2025.", "doi": "10.1016/j.stem.2025.01.012", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/40010350/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40010350/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID40010350", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "animal experimental", "decisive_perturbation": true, "endogenous": true, "direction": "contradicts", "what_it_shows": "Pre/post-mutation STRACK tracing showed driver-specific expansion of differentiation-primed stem cells and Npm1c-associated reversal toward primitive malignant states.", "what_it_does_not_show": "Early engineered murine evolution is not relapse necessity across cancers, but demonstrates that cell history and mutation alter the apparent hierarchy.", "confounders_present": [ "Early engineered murine evolution is not relapse necessity across cancers, but demonstrates that cell history and mutation alter the apparent hierarchy." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 33, "pmid": "34588223", "title": "Lineage tracing and single-cell analysis reveal proliferative Prom1+ tumour-propagating cells and their dynamic cellular transition during liver cancer progression.", "citation": "Zhou L, Yu KH, Wong TL et al. Lineage tracing and single-cell analysis reveal proliferative Prom1+ tumour-propagating cells and their dynamic cellular transition during liver cancer progression. Gut. 2022.", "doi": "10.1136/gutjnl-2021-324321", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/34588223/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34588223/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID34588223", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "animal experimental", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Prom1 lineage tracing and depletion in two intact HCC models linked clonal expansion and dynamic dedifferentiation to tumour growth; depletion impeded growth.", "what_it_does_not_show": "A lineage-state dependency in these models is not a permanently uniform marker compartment or patient-wide relapse necessity.", "confounders_present": [ "A lineage-state dependency in these models is not a permanently uniform marker compartment or patient-wide relapse necessity." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 34, "pmid": "38815020", "title": "Stem-cell states converge in multistage cutaneous squamous cell carcinoma development.", "citation": "Taylor MA, Kandyba E, Halliwill K et al. Stem-cell states converge in multistage cutaneous squamous cell carcinoma development. Science (New York, N.Y.). 2024.", "doi": "10.1126/science.adi7453", "pmcid": "PMC13492313", "url": "https://pubmed.ncbi.nlm.nih.gov/38815020/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38815020/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID38815020", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "animal experimental", "decisive_perturbation": true, "endogenous": true, "direction": "contradicts", "what_it_shows": "Integrated SCC lineage/state analyses showed chemotherapy suppressing proliferation and activating plasticity; manipulating differentiation enhanced cell-cycle-inhibitor responses.", "what_it_does_not_show": "Treatment-induced state movement challenges stability but does not establish that all tumour cells are equivalently plastic or that the same switch governs every cancer.", "confounders_present": [ "Treatment-induced state movement challenges stability but does not establish that all tumour cells are equivalently plastic or that the same switch governs every cancer." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 35, "pmid": "32080185", "title": "Tracing tumorigenesis in a solid tumor model at single-cell resolution.", "citation": "Praktiknjo SD, Obermayer B, Zhu Q et al. Tracing tumorigenesis in a solid tumor model at single-cell resolution. Nature communications. 2020.", "doi": "10.1038/s41467-020-14777-0", "pmcid": "PMC7033116", "url": "https://pubmed.ncbi.nlm.nih.gov/32080185/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32080185/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID32080185", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal experimental", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Single-cell and lineage analyses in a defined salivary-gland SCC mouse model mapped a reproducible basal-to-stem-like-to-luminal trajectory.", "what_it_does_not_show": "A developmental trajectory inferred with profiling is not ablation-defined necessity; a genetically defined model has restricted generalizability.", "confounders_present": [ "A developmental trajectory inferred with profiling is not ablation-defined necessity; a genetically defined model has restricted generalizability." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 36, "pmid": "37966117", "title": "FXYD3 functionally demarcates an ancestral breast cancer stem cell subpopulation with features of drug-tolerant persisters.", "citation": "Li M, Nishimura T, Takeuchi Y et al. FXYD3 functionally demarcates an ancestral breast cancer stem cell subpopulation with features of drug-tolerant persisters. The Journal of clinical investigation. 2023.", "doi": "10.1172/JCI166666", "pmcid": "PMC10645391", "url": "https://pubmed.ncbi.nlm.nih.gov/37966117/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37966117/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID37966117", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human experimental", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "TNBC profiling identified FXYD3-positive ancestral/persister-like cells that persisted during neoadjuvant therapy and were sensitive to Na/K-pump inhibitors.", "what_it_does_not_show": "Clinical persistence is associative and pump inhibitors affect more than CSC-specific functions; selective CSC elimination improving patient relapse-free survival was not established.", "confounders_present": [ "Clinical persistence is associative and pump inhibitors affect more than CSC-specific functions; selective CSC elimination improving patient relapse-free survival was not established." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 37, "pmid": "19570512", "title": "Monoclonal antibody-mediated targeting of CD123, IL-3 receptor alpha chain, eliminates human acute myeloid leukemic stem cells.", "citation": "Jin L, Lee EM, Ramshaw HS et al. Monoclonal antibody-mediated targeting of CD123, IL-3 receptor alpha chain, eliminates human acute myeloid leukemic stem cells. Cell stem cell. 2009.", "doi": "10.1016/j.stem.2009.04.018", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/19570512/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/19570512/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID19570512", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human experimental", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Anti-CD123 treatment reduced human AML xenograft engraftment and established disease burden, impaired secondary transplantation and improved mouse survival.", "what_it_does_not_show": "Homing, cytokine blockade and innate effector activation are intertwined; a mouse efficacy experiment does not isolate a fixed population's necessity for human cure.", "confounders_present": [ "Homing, cytokine blockade and innate effector activation are intertwined; a mouse efficacy experiment does not isolate a fixed population's necessity for human cure." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 38, "pmid": "31374198", "title": "Interconversion between Tumorigenic and Differentiated States in Acute Myeloid Leukemia.", "citation": "McKenzie MD, Ghisi M, Oxley EP et al. Interconversion between Tumorigenic and Differentiated States in Acute Myeloid Leukemia. Cell stem cell. 2019.", "doi": "10.1016/j.stem.2019.07.001", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/31374198/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31374198/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID31374198", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4", "SC5" ], "favors_models": [], "evidence_class": "Strong", "system": "animal experimental", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "Perturbing endogenous PU.1 or withdrawing differentiation treatment allowed mature AML cells in murine and human models to regain clonogenic/leukemogenic activity.", "what_it_does_not_show": "This does not show unrestricted reversal in all AML genotypes, but directly challenges irreversible differentiation even in a prototypical hierarchical malignancy.", "confounders_present": [ "This does not show unrestricted reversal in all AML genotypes, but directly challenges irreversible differentiation even in a prototypical hierarchical malignancy." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 39, "pmid": "25209969", "title": "Using heterogeneity of the patient-derived xenograft model to identify the chemoresistant population in ovarian cancer.", "citation": "Dobbin ZC, Katre AA, Steg AD et al. Using heterogeneity of the patient-derived xenograft model to identify the chemoresistant population in ovarian cancer. Oncotarget. 2014.", "doi": "10.18632/oncotarget.2373", "pmcid": "PMC4226719", "url": "https://pubmed.ncbi.nlm.nih.gov/25209969/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25209969/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID25209969", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human experimental", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Ovarian PDX tumours retained heterogeneity and clinical response patterns; carboplatin/paclitaxel enriched stem-associated populations without making persisters exclusively those populations.", "what_it_does_not_show": "Marker enrichment after treatment does not identify uniquely causal relapse cells or distinguish selection from induced plasticity.", "confounders_present": [ "Marker enrichment after treatment does not identify uniquely causal relapse cells or distinguish selection from induced plasticity." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 40, "pmid": "36450983", "title": "Ras drives malignancy through stem cell crosstalk with the microenvironment.", "citation": "Yuan S, Stewart KS, Yang Y et al. Ras drives malignancy through stem cell crosstalk with the microenvironment. Nature. 2022.", "doi": "10.1038/s41586-022-05475-6", "pmcid": "PMC9750880", "url": "https://pubmed.ncbi.nlm.nih.gov/36450983/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36450983/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID36450983", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "animal experimental", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Clonal HRAS-mutant skin models and functional pathway tests linked dynamic CSC-stromal signalling, angiogenesis and metabolic signalling to malignant transition.", "what_it_does_not_show": "Interdependent niche signals support a contextual mechanism rather than a cell-intrinsic immutable hierarchy or pan-cancer necessity.", "confounders_present": [ "Interdependent niche signals support a contextual mechanism rather than a cell-intrinsic immutable hierarchy or pan-cancer necessity." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 41, "pmid": "30568172", "title": "Single cell analysis of clonal architecture in acute myeloid leukaemia.", "citation": "Potter N, Miraki-Moud F, Ermini L et al. Single cell analysis of clonal architecture in acute myeloid leukaemia. Leukemia. 2019.", "doi": "10.1038/s41375-018-0319-2", "pmcid": "PMC6451634", "url": "https://pubmed.ncbi.nlm.nih.gov/30568172/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30568172/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID30568172", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human experimental", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Single-cell mutation analysis and xenografts showed branching AML subclones, pre-leukemic variants and preferential but variable regenerating clones.", "what_it_does_not_show": "Genetic ancestry and engraftment do not equate to fixed phenotypic stem hierarchy or independently establish post-treatment patient relapse necessity.", "confounders_present": [ "Genetic ancestry and engraftment do not equate to fixed phenotypic stem hierarchy or independently establish post-treatment patient relapse necessity." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 42, "pmid": "26832662", "title": "miR-126 Regulates Distinct Self-Renewal Outcomes in Normal and Malignant Hematopoietic Stem Cells.", "citation": "Lechman ER, Gentner B, Ng SW et al. miR-126 Regulates Distinct Self-Renewal Outcomes in Normal and Malignant Hematopoietic Stem Cells. Cancer cell. 2016.", "doi": "10.1016/j.ccell.2015.12.011", "pmcid": "PMC4749543", "url": "https://pubmed.ncbi.nlm.nih.gov/26832662/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26832662/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID27070706" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID26832662", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human experimental", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Functional miR-126 manipulation regulated primary AML self-renewal, differentiation and quiescence through PI3K/AKT/MTOR-associated signalling in vivo.", "what_it_does_not_show": "The pathway also affects normal HSCs differently; functional perturbation in transplanted systems is not exclusive clinical LSC necessity, and an erratum is linked.", "confounders_present": [ "The pathway also affects normal HSCs differently; functional perturbation in transplanted systems is not exclusive clinical LSC necessity, and an erratum is linked." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [ "Erratum PMID27070706 is a notice, not a second primary study." ] }, { "n": 43, "pmid": "28487542", "title": "Abundant and equipotent founder cells establish and maintain acute lymphoblastic leukaemia.", "citation": "Elder A, Bomken S, Wilson I et al. Abundant and equipotent founder cells establish and maintain acute lymphoblastic leukaemia. Leukemia. 2017.", "doi": "10.1038/leu.2017.140", "pmcid": "PMC5558874", "url": "https://pubmed.ncbi.nlm.nih.gov/28487542/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/28487542/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID28487542", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC4", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "human experimental", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "Barcoded primary ALL blasts showed many approximately equipotent founders contributing through serial transplants rather than a rare dominant apex.", "what_it_does_not_show": "Transplant activity is host-conditioned; this challenges rarity/exclusivity in ALL without showing that every native blast has identical fate in patients.", "confounders_present": [ "Transplant activity is host-conditioned; this challenges rarity/exclusivity in ALL without showing that every native blast has identical fate in patients." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 44, "pmid": "31146720", "title": "Lineage relationship between prostate adenocarcinoma and small cell carcinoma.", "citation": "Kanan AD, Corey E, Vêncio RZN et al. Lineage relationship between prostate adenocarcinoma and small cell carcinoma. BMC cancer. 2019.", "doi": "10.1186/s12885-019-5680-7", "pmcid": "PMC6543672", "url": "https://pubmed.ncbi.nlm.nih.gov/31146720/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31146720/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID31146720", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human experimental", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Prostate small-cell PDXs expressed reprogramming factors, and factor transfection altered expression and stem-like colony phenotypes.", "what_it_does_not_show": "Forced transcription-factor expression and colonies establish plausibility, not natural lineage conversion or fixed CSC dependence.", "confounders_present": [ "Forced transcription-factor expression and colonies establish plausibility, not natural lineage conversion or fixed CSC dependence." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 45, "pmid": "41545197", "title": "LY6D identifies persistent stem-like cells driving pancreatic tumourigenesis.", "citation": "Shi J, Wang X, Tang Y et al. LY6D identifies persistent stem-like cells driving pancreatic tumourigenesis. Gut. 2026.", "doi": "10.1136/gutjnl-2025-336460", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/41545197/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/41545197/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID41545197", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "animal experimental", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Ly6d genetic perturbation in KRAS-driven pancreatic models affected a persistent gastric-like lineage and delayed tumourigenesis; human expression correlated with prognosis.", "what_it_does_not_show": "A genetic lineage program and OXPHOS dependency do not prove that a discrete cell population is universally necessary or that patient relapse is prevented by targeting it.", "confounders_present": [ "A genetic lineage program and OXPHOS dependency do not prove that a discrete cell population is universally necessary or that patient relapse is prevented by targeting it." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 46, "pmid": "40859055", "title": "EMT-ciliary signaling in quasi-mesenchymal-stem-like cells drives therapeutic resistance and is a druggable vulnerability in triple-negative breast cancer.", "citation": "Tessier CE, Derrien J, Dupuy AMM et al. EMT-ciliary signaling in quasi-mesenchymal-stem-like cells drives therapeutic resistance and is a druggable vulnerability in triple-negative breast cancer. EMBO molecular medicine. 2025.", "doi": "10.1038/s44321-025-00289-1", "pmcid": "PMC12514032", "url": "https://pubmed.ncbi.nlm.nih.gov/40859055/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40859055/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID40859055", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human experimental", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "TNBC organoids retained EMT-associated ciliated stem-like survivors after chemotherapy; genetic cilia ablation and inhibitors suppressed resistance.", "what_it_does_not_show": "Organoid chemoresistance and NFkB-associated killing are not selective in-patient CSC eradication or a demonstration of permanently fixed hierarchy.", "confounders_present": [ "Organoid chemoresistance and NFkB-associated killing are not selective in-patient CSC eradication or a demonstration of permanently fixed hierarchy." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 47, "pmid": "42330962", "title": "Lineage plasticity driven by GATA6 loss fuels colorectal cancer metastasis.", "citation": "Goto S, Deshpande V, Yilmaz ÖH et al. Lineage plasticity driven by GATA6 loss fuels colorectal cancer metastasis. Cell stem cell. 2026.", "doi": "10.1016/j.stem.2026.05.013", "pmcid": "PMC13499791", "url": "https://pubmed.ncbi.nlm.nih.gov/42330962/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/42330962/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID42330962", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "animal experimental", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "GATA6 loss in orthotopic CRC organoid models increased metastatic plasticity and LGR5-negative states with little primary-growth change.", "what_it_does_not_show": "Genetic reprogramming shows context-specific metastatic regulation; serial transplant selection and native patient translation remain limits.", "confounders_present": [ "Genetic reprogramming shows context-specific metastatic regulation; serial transplant selection and native patient translation remain limits." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 48, "pmid": "32396863", "title": "Zonation of Ribosomal DNA Transcription Defines a Stem Cell Hierarchy in Colorectal Cancer.", "citation": "Morral C, Stanisavljevic J, Hernando-Momblona X et al. Zonation of Ribosomal DNA Transcription Defines a Stem Cell Hierarchy in Colorectal Cancer. Cell stem cell. 2020.", "doi": "10.1016/j.stem.2020.04.012", "pmcid": "PMC9006079", "url": "https://pubmed.ncbi.nlm.nih.gov/32396863/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32396863/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID32396863", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human experimental", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "POLR1A-high biosynthetic CRC compartments spanned LGR5-positive and negative cells; genetic population ablation imposed irreversible growth arrest in the reported systems.", "what_it_does_not_show": "Abstract-level access does not establish every model's endogenous status or exclude biosynthesis-dependent general toxicity; this functional compartment is broader than LGR5 identity.", "confounders_present": [ "Abstract-level access does not establish every model's endogenous status or exclude biosynthesis-dependent general toxicity; this functional compartment is broader than LGR5 identity." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 49, "pmid": "29228234", "title": "Tgfbr2 inactivation facilitates cellular plasticity and development of Pten-null prostate cancer.", "citation": "Zhao W, Zhu Q, Tan P et al. Tgfbr2 inactivation facilitates cellular plasticity and development of Pten-null prostate cancer. Journal of molecular cell biology. 2018.", "doi": "10.1093/jmcb/mjx052", "pmcid": "PMC6161409", "url": "https://pubmed.ncbi.nlm.nih.gov/29228234/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29228234/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID29228234", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "animal experimental", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Combined Pten/Tgfbr2 perturbation increased reprogramming, rapid prostate tumour development and early mortality with BMP/stemness-associated signalling.", "what_it_does_not_show": "Multi-pathway genetic changes are not selective ablation of a fixed CSC population; survival associations do not establish human mechanistic mediation.", "confounders_present": [ "Multi-pathway genetic changes are not selective ablation of a fixed CSC population; survival associations do not establish human mechanistic mediation." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 50, "pmid": "18202660", "title": "Identification of cells initiating human melanomas.", "citation": "Schatton T, Murphy GF, Frank NY et al. Identification of cells initiating human melanomas. Nature. 2008.", "doi": "10.1038/nature06489", "pmcid": "PMC3660705", "url": "https://pubmed.ncbi.nlm.nih.gov/18202660/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/18202660/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID18202660", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "human experimental", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "ABCB5-enriched melanoma cells showed serial xenograft self-renewal and antibody targeting inhibited established tumour growth.", "what_it_does_not_show": "Host and assay conditions constrain rarity; antibody-mediated cytotoxicity and ABCB5 functions do not establish universal exclusive endogenous CSC maintenance.", "confounders_present": [ "Host and assay conditions constrain rarity; antibody-mediated cytotoxicity and ABCB5 functions do not establish universal exclusive endogenous CSC maintenance." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 51, "pmid": "34143978", "title": "Evolutionary predictability of genetic versus nongenetic resistance to anticancer drugs in melanoma.", "citation": "Marin-Bejar O, Rogiers A, Dewaele M et al. Evolutionary predictability of genetic versus nongenetic resistance to anticancer drugs in melanoma. Cancer cell. 2021.", "doi": "10.1016/j.ccell.2021.05.015", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/34143978/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34143978/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID34143978", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human experimental", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "FAK inhibition depleted a transient neural-crest-like residual melanoma state and delayed xenograft relapse, with escape favouring genetic resistance.", "what_it_does_not_show": "A drug acting on a signalling network is not perfectly state-specific; delayed rather than abolished relapse illustrates alternate resistance routes.", "confounders_present": [ "A drug acting on a signalling network is not perfectly state-specific; delayed rather than abolished relapse illustrates alternate resistance routes." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 52, "pmid": "26494317", "title": "Overshoot during phenotypic switching of cancer cell populations.", "citation": "Sellerio AL, Ciusani E, Ben-Moshe NB et al. Overshoot during phenotypic switching of cancer cell populations. Scientific reports. 2015.", "doi": "10.1038/srep15464", "pmcid": "PMC4616026", "url": "https://pubmed.ncbi.nlm.nih.gov/26494317/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26494317/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID26494317", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human experimental", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "Marker-sorted melanoma populations transiently overshot stem-marker equilibrium, consistent with regulated phenotypic switching after depletion.", "what_it_does_not_show": "Marker dynamics and a regulatory model do not alone prove tumour-propagating function or endogenous relapse prevention failure.", "confounders_present": [ "Marker dynamics and a regulatory model do not alone prove tumour-propagating function or endogenous relapse prevention failure." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 53, "pmid": "24934811", "title": "ABCB5 maintains melanoma-initiating cells through a proinflammatory cytokine signaling circuit.", "citation": "Wilson BJ, Saab KR, Ma J et al. ABCB5 maintains melanoma-initiating cells through a proinflammatory cytokine signaling circuit. Cancer research. 2014.", "doi": "10.1158/0008-5472.CAN-14-0582", "pmcid": "PMC4119553", "url": "https://pubmed.ncbi.nlm.nih.gov/24934811/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/24934811/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID24934811", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human experimental", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "ABCB5 blockade altered an IL1/IL8/CXCR1 paracrine circuit, induced differentiation, reversed drug resistance and impaired melanoma growth in vivo.", "what_it_does_not_show": "Cytokine interactions with negative cells favour a network dependency; inhibition does not establish permanently discrete CSC identity or clinical cure.", "confounders_present": [ "Cytokine interactions with negative cells favour a network dependency; inhibition does not establish permanently discrete CSC identity or clinical cure." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 54, "pmid": "32803272", "title": "The acidic tumor microenvironment drives a stem-like phenotype in melanoma cells.", "citation": "Andreucci E, Peppicelli S, Ruzzolini J et al. The acidic tumor microenvironment drives a stem-like phenotype in melanoma cells. Journal of molecular medicine (Berlin, Germany). 2020.", "doi": "10.1007/s00109-020-01959-y", "pmcid": "PMC7525286", "url": "https://pubmed.ncbi.nlm.nih.gov/32803272/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32803272/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID32803272", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human experimental", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "Chronic extracellular acidosis increased melanoma stem-associated and tumour-initiating properties, with a reversible phenotype linked to EMT.", "what_it_does_not_show": "Artificial environmental adaptation and initiation assays establish plastic potential rather than the rate or necessity of native patient state switching.", "confounders_present": [ "Artificial environmental adaptation and initiation assays establish plastic potential rather than the rate or necessity of native patient state switching." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 55, "pmid": "39933514", "title": "Lactate controls cancer stemness and plasticity through epigenetic regulation.", "citation": "Nguyen NTB, Gevers S, Kok RNU et al. Lactate controls cancer stemness and plasticity through epigenetic regulation. Cell metabolism. 2025.", "doi": "10.1016/j.cmet.2025.01.002", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/39933514/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39933514/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID39933514", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human experimental", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "Reporter-tracked human intestinal tumour organoids showed lactate suppressing differentiation and inducing a proliferative stem state through acetylation/MYC-associated regulation.", "what_it_does_not_show": "Organoid transitions and candidate BRD4 targeting do not demonstrate prevention of patient relapse or a unique physiological lactate mechanism.", "confounders_present": [ "Organoid transitions and candidate BRD4 targeting do not demonstrate prevention of patient relapse or a unique physiological lactate mechanism." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 56, "pmid": "35798028", "title": "Cell-matrix interface regulates dormancy in human colon cancer stem cells.", "citation": "Ohta Y, Fujii M, Takahashi S et al. Cell-matrix interface regulates dormancy in human colon cancer stem cells. Nature. 2022.", "doi": "10.1038/s41586-022-05043-y", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/35798028/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35798028/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID35798028", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human experimental", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Intravital human CRC organoid xenograft tracing linked pre-existing LGR5/p27 dormancy to survival and post-chemotherapy expansion; COL17A1 loss and YAP interference altered sensitivity/regrowth.", "what_it_does_not_show": "Human-origin transplanted systems and niche signalling do not prove a fixed population's necessity in patients; delaying regrowth is not universal eradication.", "confounders_present": [ "Human-origin transplanted systems and niche signalling do not prove a fixed population's necessity in patients; delaying regrowth is not universal eradication." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 57, "pmid": "33945793", "title": "CD276 expression enables squamous cell carcinoma stem cells to evade immune surveillance.", "citation": "Wang C, Li Y, Jia L et al. CD276 expression enables squamous cell carcinoma stem cells to evade immune surveillance. Cell stem cell. 2021.", "doi": "10.1016/j.stem.2021.04.011", "pmcid": "PMC8419062", "url": "https://pubmed.ncbi.nlm.nih.gov/33945793/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33945793/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID33945793", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "animal experimental", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Anti-CD276 eliminated stem-enriched SCC cells through CD8-dependent immunity and reduced tumour growth and nodal metastases in mouse HNSCC.", "what_it_does_not_show": "Immune-mediated targeting remodels several tumour states; human CD276 expression is not patient evidence that a stable CSC compartment is uniquely necessary.", "confounders_present": [ "Immune-mediated targeting remodels several tumour states; human CD276 expression is not patient evidence that a stable CSC compartment is uniquely necessary." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 58, "pmid": "31474569", "title": "Single-Cell Transcriptomics in Medulloblastoma Reveals Tumor-Initiating Progenitors and Oncogenic Cascades during Tumorigenesis and Relapse.", "citation": "Zhang L, He X, Liu X et al. Single-Cell Transcriptomics in Medulloblastoma Reveals Tumor-Initiating Progenitors and Oncogenic Cascades during Tumorigenesis and Relapse. Cancer cell. 2019.", "doi": "10.1016/j.ccell.2019.07.009", "pmcid": "PMC6760242", "url": "https://pubmed.ncbi.nlm.nih.gov/31474569/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31474569/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID31474569", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "animal experimental", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "SHH medulloblastoma studies identified OLIG2 progenitors that changed to quiescent stem-like states; depletion/deletion impeded initiation and pathway combinations arrested growth.", "what_it_does_not_show": "Therapy-resistant enrichment is not direct selective relapse prevention in children; stem-like function is developmentally and disease-context dependent.", "confounders_present": [ "Therapy-resistant enrichment is not direct selective relapse prevention in children; stem-like function is developmentally and disease-context dependent." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 59, "pmid": "21075313", "title": "Phenotypic heterogeneity among tumorigenic melanoma cells from patients that is reversible and not hierarchically organized.", "citation": "Quintana E, Shackleton M, Foster HR et al. Phenotypic heterogeneity among tumorigenic melanoma cells from patients that is reversible and not hierarchically organized. Cancer cell. 2010.", "doi": "10.1016/j.ccr.2010.10.012", "pmcid": "PMC3031091", "url": "https://pubmed.ncbi.nlm.nih.gov/21075313/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/21075313/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID21075313", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC4", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "human experimental", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "Direct patient melanoma cells frequently initiated serially transplantable tumours in permissive hosts; diverse markers failed to separate a large non-tumorigenic compartment and were reversible.", "what_it_does_not_show": "A transplantation counterexample challenges rarity and marker exclusivity, but does not establish identical native fate for every melanoma cell.", "confounders_present": [ "A transplantation counterexample challenges rarity and marker exclusivity, but does not establish identical native fate for every melanoma cell." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [ "Permissive NSG transplantation platform also used in PMID19052619; not a new assay class." ] }, { "n": 60, "pmid": "36880956", "title": "Ablation of p57+ Quiescent Cancer Stem Cells Suppresses Recurrence after Chemotherapy of Intestinal Tumors.", "citation": "Oka T, Higa T, Sugahara O et al. Ablation of p57+ Quiescent Cancer Stem Cells Suppresses Recurrence after Chemotherapy of Intestinal Tumors. Cancer research. 2023.", "doi": "10.1158/0008-5472.CAN-22-2578", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/36880956/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36880956/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID36880956", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal experimental", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "A syngeneic orthotopic intestinal organoid model identified quiescent p57-positive lineages surviving chemotherapy; their ablation suppressed post-treatment regrowth.", "what_it_does_not_show": "This is a transplanted model and demonstrates suppression, not universal complete relapse prevention or an invariant CSC pool across tumours.", "confounders_present": [ "This is a transplanted model and demonstrates suppression, not universal complete relapse prevention or an invariant CSC pool across tumours." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 61, "pmid": "30297799", "title": "A slow-cycling LGR5 tumour population mediates basal cell carcinoma relapse after therapy.", "citation": "Sánchez-Danés A, Larsimont JC, Liagre M et al. A slow-cycling LGR5 tumour population mediates basal cell carcinoma relapse after therapy. Nature. 2018.", "doi": "10.1038/s41586-018-0603-3", "pmcid": "PMC6295195", "url": "https://pubmed.ncbi.nlm.nih.gov/30297799/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30297799/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID30297799", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 7:Main text (unsectioned body paragraphs):paragraph5, 7:Main text (unsectioned body paragraphs):paragraph17, 7:Main text (unsectioned body paragraphs):paragraph18, 7:Main text (unsectioned body paragraphs):paragraph19, 7:Main text (unsectioned body paragraphs):paragraph21. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "animal experimental", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "In engineered BCC models, Lgr5-positive persisters drove regrowth after vismodegib withdrawal; combined treatment removed most lesions and dual Wnt/Hedgehog inhibition prevented recurrence over the tested four-week follow-up.", "what_it_does_not_show": "Human biopsies supplied phenotype/withdrawal linkage; mouse Lgr5-ablation duration was limited by normal liver toxicity, and long-term eradication was not established.", "confounders_present": [ "Human biopsies supplied phenotype/withdrawal linkage; mouse Lgr5-ablation duration was limited by normal liver toxicity, and long-term eradication was not established." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 62, "pmid": "41565826", "title": "Critical role for a high-plasticity cell state in lung cancer.", "citation": "Chan JE, Pan CH, Rub J et al. Critical role for a high-plasticity cell state in lung cancer. Nature. 2026.", "doi": "10.1038/s41586-025-09985-x", "pmcid": "PMC12960256", "url": "https://pubmed.ncbi.nlm.nih.gov/41565826/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/41565826/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "UpdateOf: PMID41278778" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID41565826", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 4:HPCS drives tumour growth and progression:paragraph0, 4:HPCS drives tumour growth and progression:paragraph3, 4:HPCS drives tumour growth and progression:paragraph5, 4:HPCS drives tumour growth and progression:paragraph7, 7:Discussion:paragraph0, 7:Discussion:paragraph1, 7:Discussion:paragraph2, 7:Discussion:paragraph3, 3:Non-HPCS cells can acquire the HPCS. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "animal experimental", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Autochthonous lung tumour reporters, tracing and two ablation approaches showed a high-plasticity hub driving progression, burden and resistant states.", "what_it_does_not_show": "Non-HPCS cells can acquire HPCS; suppression does not establish an immutable population, pan-cancer clinical necessity or durable human cure. The linked earlier version is not a second independent report.", "confounders_present": [ "Non-HPCS cells can acquire HPCS; suppression does not establish an immutable population, pan-cancer clinical necessity or durable human cure. The linked earlier version is not a second independent report." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [ "Reporter recombination incomplete in some autochthonous tumours; rescue of interpretation through a clonal allograft is not independent patient confirmation." ] }, { "n": 63, "pmid": "42386981", "title": "TROP2 targeting reveals therapy-driven cell state dynamics in colorectal cancer.", "citation": "Vaquero-Siguero N, Georgakopoulos N, Puschhof MC et al. TROP2 targeting reveals therapy-driven cell state dynamics in colorectal cancer. Nature. 2026.", "doi": "10.1038/s41586-026-10705-2", "pmcid": "PMC13518220", "url": "https://pubmed.ncbi.nlm.nih.gov/42386981/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/42386981/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID42386981", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 4:TROP2 targeting and cell state remodelling:paragraph0, 5:Chemotherapy-induced TROP2 and plasticity:paragraph0, 5:Chemotherapy-induced TROP2 and plasticity:paragraph3, 5:Chemotherapy-induced TROP2 and plasticity:paragraph4. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human experimental", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Patient-derived CRC models showed context-dependent TROP2-positive stemness, chemotherapy-induced state redistribution and enhanced efficacy of combination TROP2-directed treatment.", "what_it_does_not_show": "State-specific vulnerability and model efficacy do not demonstrate permanent cell identity or relapse-free survival benefit in patients.", "confounders_present": [ "State-specific vulnerability and model efficacy do not demonstrate permanent cell identity or relapse-free survival benefit in patients." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 64, "pmid": "42557330", "title": "ZFP36L2 orchestrates stress-adaptive plasticity in regeneration and cancer.", "citation": "Jiang Q, Raghavan MS, Rodriguez AM et al. ZFP36L2 orchestrates stress-adaptive plasticity in regeneration and cancer. Nature. 2026.", "doi": "10.1038/s41586-026-10890-0", "pmcid": "PMC13600930", "url": "https://pubmed.ncbi.nlm.nih.gov/42557330/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/42557330/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID42557330", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 4:ZFP36L2 loss drives non-canonical fates, 7:Discussion. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human experimental", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "ZFP36L2 loss impaired canonical LGR5 re-entry/metastatic growth while promoting alternative heterogeneous fates; mouse regeneration tests also implicated stress-responsive dedifferentiation.", "what_it_does_not_show": "Canonical stem-state dependency can be bypassed by alternative plasticity; poor-outcome associations are not a pan-cancer necessity/sufficiency test.", "confounders_present": [ "Canonical stem-state dependency can be bypassed by alternative plasticity; poor-outcome associations are not a pan-cancer necessity/sufficiency test." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 65, "pmid": "23225641", "title": "Intravital imaging of cancer stem cell plasticity in mammary tumors.", "citation": "Zomer A, Ellenbroek SI, Ritsma L et al. Intravital imaging of cancer stem cell plasticity in mammary tumors. Stem cells (Dayton, Ohio). 2013.", "doi": "10.1002/stem.1296", "pmcid": "PMC3744756", "url": "https://pubmed.ncbi.nlm.nih.gov/23225641/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/23225641/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID23225641", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "animal experimental", "decisive_perturbation": true, "endogenous": true, "direction": "contradicts", "what_it_shows": "Intravital lineage tracing in unperturbed mammary tumours documented disappearance of existing stem-like contributors and formation of new ones.", "what_it_does_not_show": "A dynamic lineage contribution supports plastic stemness, without measuring universal patient transition rates or showing every cancer lacks a hierarchy.", "confounders_present": [ "A dynamic lineage contribution supports plastic stemness, without measuring universal patient transition rates or showing every cancer lacks a hierarchy." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 66, "pmid": "30992437", "title": "Stem cell-associated heterogeneity in Glioblastoma results from intrinsic tumor plasticity shaped by the microenvironment.", "citation": "Dirkse A, Golebiewska A, Buder T et al. Stem cell-associated heterogeneity in Glioblastoma results from intrinsic tumor plasticity shaped by the microenvironment. Nature communications. 2019.", "doi": "10.1038/s41467-019-09853-z", "pmcid": "PMC6467886", "url": "https://pubmed.ncbi.nlm.nih.gov/30992437/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30992437/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID30992437", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human experimental", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "GBM stem-marker populations exhibited reversible microenvironment-instructed transitions; faster reconstitution of heterogeneity conferred an in-vivo growth advantage.", "what_it_does_not_show": "Model-based and transplanted growth tests challenge discrete marker identity but do not exclude functionally important stem-like states in native gliomas.", "confounders_present": [ "Model-based and transplanted growth tests challenge discrete marker identity but do not exclude functionally important stem-like states in native gliomas." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 67, "pmid": "30177776", "title": "Stem cell functionality is microenvironmentally defined during tumour expansion and therapy response in colon cancer.", "citation": "Lenos KJ, Miedema DM, Lodestijn SC et al. Stem cell functionality is microenvironmentally defined during tumour expansion and therapy response in colon cancer. Nature cell biology. 2018.", "doi": "10.1038/s41556-018-0179-z", "pmcid": "PMC6163039", "url": "https://pubmed.ncbi.nlm.nih.gov/30177776/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30177776/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID30177776", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human experimental", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "Time-resolved colon xenograft clones linked functional stemness to edge location and fibroblast-derived osteopontin, including after chemotherapy.", "what_it_does_not_show": "Quantitative model fit is not unique proof; transplanted tissue and stromal interactions limit inference about a stable intrinsic patient hierarchy.", "confounders_present": [ "Quantitative model fit is not unique proof; transplanted tissue and stromal interactions limit inference about a stable intrinsic patient hierarchy." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 68, "pmid": "24909994", "title": "SOX2 controls tumour initiation and cancer stem-cell functions in squamous-cell carcinoma.", "citation": "Boumahdi S, Driessens G, Lapouge G et al. SOX2 controls tumour initiation and cancer stem-cell functions in squamous-cell carcinoma. Nature. 2014.", "doi": "10.1038/nature13305", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/24909994/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/24909994/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID24909994", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "animal experimental", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Sox2 deletion reduced chemical skin tumour formation; lineage ablation and conditional deletion in established papillomas/SCCs caused regression.", "what_it_does_not_show": "SOX2 regulates multiple survival and lineage functions; a strong skin-model dependency does not establish pan-cancer fixed-CSC necessity.", "confounders_present": [ "SOX2 regulates multiple survival and lineage functions; a strong skin-model dependency does not establish pan-cancer fixed-CSC necessity." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] } ], "verification_summary": { "load_bearing_claims_checked": 74, "verified": 74, "unverified": 0, "contradicted": 0, "note": "Verified attribution is distinct from mechanism truth or complete body access." }, "factual_issues_found": [], "cap_rules_applied": [], "cap_precedence_resolutions": [ { "collision": "Perturbation in a defined setting versus broader inference", "subclaim_scope_cap_binds_on": "Discrete self-renewing cancer stem-cell populations organized in stable hierarchies are necessary for tumour maintenance and post-treatment relapse across human cancers.", "subclaim_scope_threshold_binds_on": "The precise experimentally tested subclaim scope", "resolution": "The cancer rubric gives endogenous lineage tracing and precise disease-relevant perturbation substantial causal weight; SC1 reaches Ζ and defined maintenance/relapse reach Ε. Its statement that CSC models often have context-specific validity is applied explicitly to those scopes. Γ restrictions on sphere/marker/xenograft-only inference do not erase the assembled native evidence. SC4 and SC5 stop on unmet broader threshold burdens and contradictory stability predictions, without an invented literal hard cap or treating the absence of an RCT as dispositive.", "note": "Convergent lines are assessed as a set; one weak leg is not re-capped over the assembled case." } ], "boundary_check_BGD": [ { "subclaim_id": "SC1", "field_valid_perturbation_quote": "\n- Endogenous genetic manipulation in autochthonous models\n- Patient-derived system perturbation with matched rescue AND in vivo confirmation\n- Clonal tracking demonstrating persistence of dependency through selection pressure", "qualifying_evidence_present": "yes", "qualifying_evidence_citation": "PMID19052619, PMID20048081, PMID22855427, PMID22854777, PMID28355176, PMID28468934, PMID26679053, PMID35931031, PMID34686335, PMID40010350, PMID34588223, PMID28487542, PMID41545197, PMID32396863, PMID18202660, PMID31474569, PMID21075313, PMID41565826, PMID23225641, PMID30992437, PMID30177776, PMID24909994", "gamma_hard_rules_triggered": [], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "yes", "perturbation_result_note": "Endogenous skin, intestinal and glioma tracing, supported by human-origin functional assays, independently establishes functional hierarchy/stem-like contribution in defined settings. It does not establish permanent marker identity in every cancer.", "ceiling_from_boundary_check": "Δ or higher" }, { "subclaim_id": "SC2", "field_valid_perturbation_quote": "\n- Endogenous genetic manipulation in autochthonous models\n- Patient-derived system perturbation with matched rescue AND in vivo confirmation\n- Clonal tracking demonstrating persistence of dependency through selection pressure", "qualifying_evidence_present": "yes", "qualifying_evidence_citation": "PMID23239622, PMID22855427, PMID22854777, PMID22854781, PMID28355176, PMID28358093, PMID34686335, PMID28526679, PMID34588223, PMID38815020, PMID19570512, PMID36450983, PMID26832662, PMID41545197, PMID32396863, PMID29228234, PMID18202660, PMID24934811, PMID33945793, PMID31474569, PMID30297799, PMID41565826, PMID42386981, PMID30177776, PMID24909994", "gamma_hard_rules_triggered": [], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "yes", "perturbation_result_note": "Precise Sox2, Prom1 and HPCS perturbations impair growth in defined native models. Lgr5-negative CRC maintenance and context-specific niche dependence delimit the necessity claim; CSC-like function can be required without an irreplaceable fixed population.", "ceiling_from_boundary_check": "Δ or higher" }, { "subclaim_id": "SC3", "field_valid_perturbation_quote": "\n- Endogenous genetic manipulation in autochthonous models\n- Patient-derived system perturbation with matched rescue AND in vivo confirmation\n- Clonal tracking demonstrating persistence of dependency through selection pressure", "qualifying_evidence_present": "yes", "qualifying_evidence_citation": "PMID28658204, PMID23239622, PMID22854781, PMID28355176, PMID28358093, PMID32169167, PMID36352230, PMID35773527, PMID35931031, PMID28526679, PMID30726735, PMID38815020, PMID37966117, PMID19570512, PMID25209969, PMID26832662, PMID40859055, PMID42330962, PMID34143978, PMID24934811, PMID35798028, PMID33945793, PMID31474569, PMID36880956, PMID30297799, PMID41565826, PMID42386981, PMID42557330, PMID30177776", "gamma_hard_rules_triggered": [], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "yes", "perturbation_result_note": "Glioma, BCC, p57 and residual CRC tests demonstrate treatment/stage-dependent relapse dependencies. EMP1 ablation before surgery and after seeding differ; selective Lgr5 depletion can fail to prevent CRC relapse. Clinical universal relapse prevention is not demonstrated.", "ceiling_from_boundary_check": "Δ or higher" }, { "subclaim_id": "SC4", "field_valid_perturbation_quote": "\n- Endogenous genetic manipulation in autochthonous models\n- Patient-derived system perturbation with matched rescue AND in vivo confirmation\n- Clonal tracking demonstrating persistence of dependency through selection pressure", "qualifying_evidence_present": "no", "qualifying_evidence_citation": "PMID19052619, PMID20048081, PMID18485877, PMID21498687, PMID21854987, PMID28658204, PMID23239622, PMID22854777, PMID28355176, PMID28358093, PMID28468934, PMID26679053, PMID32169167, PMID36352230, PMID35773527, PMID35931031, PMID34686335, PMID28526679, PMID30726735, PMID40010350, PMID34588223, PMID38815020, PMID37966117, PMID31374198, PMID25209969, PMID36450983, PMID28487542, PMID31146720, PMID41545197, PMID40859055, PMID42330962, PMID32396863, PMID29228234, PMID34143978, PMID26494317, PMID24934811, PMID32803272, PMID39933514, PMID35798028, PMID31474569, PMID21075313, PMID36880956, PMID41565826, PMID42386981, PMID42557330, PMID23225641, PMID30992437, PMID30177776", "gamma_hard_rules_triggered": [ "Native and functional evidence permits reversible membership; no positive cross-context immutability test." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "Permanent one-way membership remains a plausible local description, but mammary intravital tracing, AML differentiation reversal, CRC regrowth and HPCS re-entry directly contradict its broad stability prediction. The level records the unestablished general mechanism, not endorsement of stability.", "ceiling_from_boundary_check": "Γ" }, { "subclaim_id": "SC5", "field_valid_perturbation_quote": "\n- Endogenous genetic manipulation in autochthonous models\n- Patient-derived system perturbation with matched rescue AND in vivo confirmation\n- Clonal tracking demonstrating persistence of dependency through selection pressure", "qualifying_evidence_present": "no", "qualifying_evidence_citation": "PMID19052619, PMID20048081, PMID28658204, PMID28358093, PMID34686335, PMID31374198, PMID28487542, PMID18202660, PMID21075313", "gamma_hard_rules_triggered": [ "Broad fixed-population necessity is not established by the scope-matched evidence set." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "The preregistered cross-human-cancer fixed-population gate is not crossed. Strong causal successes in defined models do not establish the conjunction of stable hierarchy, irreplaceable membership and necessary maintenance/relapse across human haematological and solid cancers.", "ceiling_from_boundary_check": "Γ" } ], "thresholds_tested": [ { "subclaim_id": "SC1", "threshold": "Δ", "requirement_quoted": "Requires at least one meaningful causal perturbation showing the proposed mechanism contributes to initiation, maintenance, or relapse.", "satisfied": "yes", "supporting_evidence": [ "[6] More permissive host conditions detected tumour formation from many unselected human melanoma cells, including single-cell inocula.", "[7] Single-cell melanoma transplants revealed multiple propagating phenotypes with different capacities to reconstruct heterogeneity and resist chemotherapy.", "[16] Endogenous multicolour lineage retracing showed Lgr5-positive adenoma cells self-renewing and producing the other adenoma cell types.", "[17] Genetic clonal tracing in native skin tumours distinguished persistent stem-like and transient compartments in papillomas, with different dynamics in invasive carcinoma.", "[19] Human CRC organoid lineage tracing and selective LGR5 ablation caused regression followed by regrowth involving KRT20-lineage conversion into LGR5-positive cells.", "[21] Edited patient-derived CRC organoid xenografts showed long-term LGR5-lineage self-renewal and differentiated descendants.", "[22] CRC cells downregulated initiating-cell markers under differentiating adherent conditions yet retained serial xenograft tumour initiation and clonal contribution.", "[26] Mouse and human neoplasia showed variable conventional/regenerative stem-state admixture that adapted under acute selective pressure and tracked chemoresistance.", "[27] Marker-independent in-situ pancreatic clonal tracing found widespread clonogenic potential controlled by fibroblast proximity; stromal Hedgehog inhibition altered growth mode.", "[32] Pre/post-mutation STRACK tracing showed driver-specific expansion of differentiation-primed stem cells and Npm1c-associated reversal toward primitive malignant states.", "[33] Prom1 lineage tracing and depletion in two intact HCC models linked clonal expansion and dynamic dedifferentiation to tumour growth; depletion impeded growth.", "[43] Barcoded primary ALL blasts showed many approximately equipotent founders contributing through serial transplants rather than a rare dominant apex.", "[45] Ly6d genetic perturbation in KRAS-driven pancreatic models affected a persistent gastric-like lineage and delayed tumourigenesis; human expression correlated with prognosis.", "[48] POLR1A-high biosynthetic CRC compartments spanned LGR5-positive and negative cells; genetic population ablation imposed irreversible growth arrest in the reported systems.", "[50] ABCB5-enriched melanoma cells showed serial xenograft self-renewal and antibody targeting inhibited established tumour growth.", "[58] SHH medulloblastoma studies identified OLIG2 progenitors that changed to quiescent stem-like states; depletion/deletion impeded initiation and pathway combinations arrested growth.", "[59] Direct patient melanoma cells frequently initiated serially transplantable tumours in permissive hosts; diverse markers failed to separate a large non-tumorigenic compartment and were reversible.", "[62] Autochthonous lung tumour reporters, tracing and two ablation approaches showed a high-plasticity hub driving progression, burden and resistant states.", "[65] Intravital lineage tracing in unperturbed mammary tumours documented disappearance of existing stem-like contributors and formation of new ones.", "[66] GBM stem-marker populations exhibited reversible microenvironment-instructed transitions; faster reconstitution of heterogeneity conferred an in-vivo growth advantage.", "[67] Time-resolved colon xenograft clones linked functional stemness to edge location and fibroblast-derived osteopontin, including after chemotherapy.", "[68] Sox2 deletion reduced chemical skin tumour formation; lineage ablation and conditional deletion in established papillomas/SCCs caused regression." ], "what_would_cross_it": "" }, { "subclaim_id": "SC1", "threshold": "Ε", "requirement_quoted": "Requires context-specific causal validity with explicit limits. Cancer stem cells often belong here when a stem-like hierarchy exists in some tumor contexts but fails as a universal model.", "satisfied": "yes", "supporting_evidence": [ "[6] More permissive host conditions detected tumour formation from many unselected human melanoma cells, including single-cell inocula.", "[7] Single-cell melanoma transplants revealed multiple propagating phenotypes with different capacities to reconstruct heterogeneity and resist chemotherapy.", "[16] Endogenous multicolour lineage retracing showed Lgr5-positive adenoma cells self-renewing and producing the other adenoma cell types.", "[17] Genetic clonal tracing in native skin tumours distinguished persistent stem-like and transient compartments in papillomas, with different dynamics in invasive carcinoma.", "[19] Human CRC organoid lineage tracing and selective LGR5 ablation caused regression followed by regrowth involving KRT20-lineage conversion into LGR5-positive cells.", "[21] Edited patient-derived CRC organoid xenografts showed long-term LGR5-lineage self-renewal and differentiated descendants.", "[22] CRC cells downregulated initiating-cell markers under differentiating adherent conditions yet retained serial xenograft tumour initiation and clonal contribution.", "[26] Mouse and human neoplasia showed variable conventional/regenerative stem-state admixture that adapted under acute selective pressure and tracked chemoresistance.", "[27] Marker-independent in-situ pancreatic clonal tracing found widespread clonogenic potential controlled by fibroblast proximity; stromal Hedgehog inhibition altered growth mode.", "[32] Pre/post-mutation STRACK tracing showed driver-specific expansion of differentiation-primed stem cells and Npm1c-associated reversal toward primitive malignant states.", "[33] Prom1 lineage tracing and depletion in two intact HCC models linked clonal expansion and dynamic dedifferentiation to tumour growth; depletion impeded growth.", "[43] Barcoded primary ALL blasts showed many approximately equipotent founders contributing through serial transplants rather than a rare dominant apex.", "[45] Ly6d genetic perturbation in KRAS-driven pancreatic models affected a persistent gastric-like lineage and delayed tumourigenesis; human expression correlated with prognosis.", "[48] POLR1A-high biosynthetic CRC compartments spanned LGR5-positive and negative cells; genetic population ablation imposed irreversible growth arrest in the reported systems.", "[50] ABCB5-enriched melanoma cells showed serial xenograft self-renewal and antibody targeting inhibited established tumour growth.", "[58] SHH medulloblastoma studies identified OLIG2 progenitors that changed to quiescent stem-like states; depletion/deletion impeded initiation and pathway combinations arrested growth.", "[59] Direct patient melanoma cells frequently initiated serially transplantable tumours in permissive hosts; diverse markers failed to separate a large non-tumorigenic compartment and were reversible.", "[62] Autochthonous lung tumour reporters, tracing and two ablation approaches showed a high-plasticity hub driving progression, burden and resistant states.", "[65] Intravital lineage tracing in unperturbed mammary tumours documented disappearance of existing stem-like contributors and formation of new ones.", "[66] GBM stem-marker populations exhibited reversible microenvironment-instructed transitions; faster reconstitution of heterogeneity conferred an in-vivo growth advantage.", "[67] Time-resolved colon xenograft clones linked functional stemness to edge location and fibroblast-derived osteopontin, including after chemotherapy.", "[68] Sox2 deletion reduced chemical skin tumour formation; lineage ablation and conditional deletion in established papillomas/SCCs caused regression." ], "what_would_cross_it": "" }, { "subclaim_id": "SC1", "threshold": "Ζ", "requirement_quoted": "Requires:\n- Independent causal confirmation across models\n- Reduced viability of major alternatives\n- Relevance beyond one assay class", "satisfied": "yes", "supporting_evidence": [ "[6] More permissive host conditions detected tumour formation from many unselected human melanoma cells, including single-cell inocula.", "[7] Single-cell melanoma transplants revealed multiple propagating phenotypes with different capacities to reconstruct heterogeneity and resist chemotherapy.", "[16] Endogenous multicolour lineage retracing showed Lgr5-positive adenoma cells self-renewing and producing the other adenoma cell types.", "[17] Genetic clonal tracing in native skin tumours distinguished persistent stem-like and transient compartments in papillomas, with different dynamics in invasive carcinoma.", "[19] Human CRC organoid lineage tracing and selective LGR5 ablation caused regression followed by regrowth involving KRT20-lineage conversion into LGR5-positive cells.", "[21] Edited patient-derived CRC organoid xenografts showed long-term LGR5-lineage self-renewal and differentiated descendants.", "[22] CRC cells downregulated initiating-cell markers under differentiating adherent conditions yet retained serial xenograft tumour initiation and clonal contribution.", "[26] Mouse and human neoplasia showed variable conventional/regenerative stem-state admixture that adapted under acute selective pressure and tracked chemoresistance.", "[27] Marker-independent in-situ pancreatic clonal tracing found widespread clonogenic potential controlled by fibroblast proximity; stromal Hedgehog inhibition altered growth mode.", "[32] Pre/post-mutation STRACK tracing showed driver-specific expansion of differentiation-primed stem cells and Npm1c-associated reversal toward primitive malignant states.", "[33] Prom1 lineage tracing and depletion in two intact HCC models linked clonal expansion and dynamic dedifferentiation to tumour growth; depletion impeded growth.", "[43] Barcoded primary ALL blasts showed many approximately equipotent founders contributing through serial transplants rather than a rare dominant apex.", "[45] Ly6d genetic perturbation in KRAS-driven pancreatic models affected a persistent gastric-like lineage and delayed tumourigenesis; human expression correlated with prognosis.", "[48] POLR1A-high biosynthetic CRC compartments spanned LGR5-positive and negative cells; genetic population ablation imposed irreversible growth arrest in the reported systems.", "[50] ABCB5-enriched melanoma cells showed serial xenograft self-renewal and antibody targeting inhibited established tumour growth.", "[58] SHH medulloblastoma studies identified OLIG2 progenitors that changed to quiescent stem-like states; depletion/deletion impeded initiation and pathway combinations arrested growth.", "[59] Direct patient melanoma cells frequently initiated serially transplantable tumours in permissive hosts; diverse markers failed to separate a large non-tumorigenic compartment and were reversible.", "[62] Autochthonous lung tumour reporters, tracing and two ablation approaches showed a high-plasticity hub driving progression, burden and resistant states.", "[65] Intravital lineage tracing in unperturbed mammary tumours documented disappearance of existing stem-like contributors and formation of new ones.", "[66] GBM stem-marker populations exhibited reversible microenvironment-instructed transitions; faster reconstitution of heterogeneity conferred an in-vivo growth advantage.", "[67] Time-resolved colon xenograft clones linked functional stemness to edge location and fibroblast-derived osteopontin, including after chemotherapy.", "[68] Sox2 deletion reduced chemical skin tumour formation; lineage ablation and conditional deletion in established papillomas/SCCs caused regression." ], "what_would_cross_it": "" }, { "subclaim_id": "SC1", "threshold": "Η", "requirement_quoted": "Requires:\n- Strong endogenous evidence\n- Therapeutic or mechanistic consequence\n- Reproducibility across disease settings within the claimed scope", "satisfied": "no", "supporting_evidence": [ "[6] More permissive host conditions detected tumour formation from many unselected human melanoma cells, including single-cell inocula.", "[7] Single-cell melanoma transplants revealed multiple propagating phenotypes with different capacities to reconstruct heterogeneity and resist chemotherapy.", "[16] Endogenous multicolour lineage retracing showed Lgr5-positive adenoma cells self-renewing and producing the other adenoma cell types.", "[17] Genetic clonal tracing in native skin tumours distinguished persistent stem-like and transient compartments in papillomas, with different dynamics in invasive carcinoma.", "[19] Human CRC organoid lineage tracing and selective LGR5 ablation caused regression followed by regrowth involving KRT20-lineage conversion into LGR5-positive cells.", "[21] Edited patient-derived CRC organoid xenografts showed long-term LGR5-lineage self-renewal and differentiated descendants.", "[22] CRC cells downregulated initiating-cell markers under differentiating adherent conditions yet retained serial xenograft tumour initiation and clonal contribution.", "[26] Mouse and human neoplasia showed variable conventional/regenerative stem-state admixture that adapted under acute selective pressure and tracked chemoresistance.", "[27] Marker-independent in-situ pancreatic clonal tracing found widespread clonogenic potential controlled by fibroblast proximity; stromal Hedgehog inhibition altered growth mode.", "[32] Pre/post-mutation STRACK tracing showed driver-specific expansion of differentiation-primed stem cells and Npm1c-associated reversal toward primitive malignant states.", "[33] Prom1 lineage tracing and depletion in two intact HCC models linked clonal expansion and dynamic dedifferentiation to tumour growth; depletion impeded growth.", "[43] Barcoded primary ALL blasts showed many approximately equipotent founders contributing through serial transplants rather than a rare dominant apex.", "[45] Ly6d genetic perturbation in KRAS-driven pancreatic models affected a persistent gastric-like lineage and delayed tumourigenesis; human expression correlated with prognosis.", "[48] POLR1A-high biosynthetic CRC compartments spanned LGR5-positive and negative cells; genetic population ablation imposed irreversible growth arrest in the reported systems.", "[50] ABCB5-enriched melanoma cells showed serial xenograft self-renewal and antibody targeting inhibited established tumour growth.", "[58] SHH medulloblastoma studies identified OLIG2 progenitors that changed to quiescent stem-like states; depletion/deletion impeded initiation and pathway combinations arrested growth.", "[59] Direct patient melanoma cells frequently initiated serially transplantable tumours in permissive hosts; diverse markers failed to separate a large non-tumorigenic compartment and were reversible.", "[62] Autochthonous lung tumour reporters, tracing and two ablation approaches showed a high-plasticity hub driving progression, burden and resistant states.", "[65] Intravital lineage tracing in unperturbed mammary tumours documented disappearance of existing stem-like contributors and formation of new ones.", "[66] GBM stem-marker populations exhibited reversible microenvironment-instructed transitions; faster reconstitution of heterogeneity conferred an in-vivo growth advantage.", "[67] Time-resolved colon xenograft clones linked functional stemness to edge location and fibroblast-derived osteopontin, including after chemotherapy.", "[68] Sox2 deletion reduced chemical skin tumour formation; lineage ablation and conditional deletion in established papillomas/SCCs caused regression." ], "what_would_cross_it": "Replication of native human fate hierarchies with orthogonal functional perturbation and controls excluding lineage-marker induction artefacts." }, { "subclaim_id": "SC2", "threshold": "Δ", "requirement_quoted": "Requires at least one meaningful causal perturbation showing the proposed mechanism contributes to initiation, maintenance, or relapse.", "satisfied": "yes", "supporting_evidence": [ "[15] Lentiviral tracking within genetically stable colorectal clones revealed variable propagation and chemotherapy-selected minor or dormant lineages.", "[16] Endogenous multicolour lineage retracing showed Lgr5-positive adenoma cells self-renewing and producing the other adenoma cell types.", "[17] Genetic clonal tracing in native skin tumours distinguished persistent stem-like and transient compartments in papillomas, with different dynamics in invasive carcinoma.", "[18] Pulse-chase and transgene-directed ablation identified an endogenous glioma subset sustaining regrowth after temozolomide; chronic ganciclovir arrested growth and combination treatment impeded development.", "[19] Human CRC organoid lineage tracing and selective LGR5 ablation caused regression followed by regrowth involving KRT20-lineage conversion into LGR5-positive cells.", "[20] Selective Lgr5 ablation restricted primary CRC growth without regression while negative cells replenished the pool; liver metastases showed stronger Lgr5 dependence.", "[27] Marker-independent in-situ pancreatic clonal tracing found widespread clonogenic potential controlled by fibroblast proximity; stromal Hedgehog inhibition altered growth mode.", "[28] Serial pancreatic xenografts were maintained by successive transiently active initiating clones with little overlap between generations.", "[33] Prom1 lineage tracing and depletion in two intact HCC models linked clonal expansion and dynamic dedifferentiation to tumour growth; depletion impeded growth.", "[34] Integrated SCC lineage/state analyses showed chemotherapy suppressing proliferation and activating plasticity; manipulating differentiation enhanced cell-cycle-inhibitor responses.", "[37] Anti-CD123 treatment reduced human AML xenograft engraftment and established disease burden, impaired secondary transplantation and improved mouse survival.", "[40] Clonal HRAS-mutant skin models and functional pathway tests linked dynamic CSC-stromal signalling, angiogenesis and metabolic signalling to malignant transition.", "[42] Functional miR-126 manipulation regulated primary AML self-renewal, differentiation and quiescence through PI3K/AKT/MTOR-associated signalling in vivo.", "[45] Ly6d genetic perturbation in KRAS-driven pancreatic models affected a persistent gastric-like lineage and delayed tumourigenesis; human expression correlated with prognosis.", "[48] POLR1A-high biosynthetic CRC compartments spanned LGR5-positive and negative cells; genetic population ablation imposed irreversible growth arrest in the reported systems.", "[49] Combined Pten/Tgfbr2 perturbation increased reprogramming, rapid prostate tumour development and early mortality with BMP/stemness-associated signalling.", "[50] ABCB5-enriched melanoma cells showed serial xenograft self-renewal and antibody targeting inhibited established tumour growth.", "[53] ABCB5 blockade altered an IL1/IL8/CXCR1 paracrine circuit, induced differentiation, reversed drug resistance and impaired melanoma growth in vivo.", "[57] Anti-CD276 eliminated stem-enriched SCC cells through CD8-dependent immunity and reduced tumour growth and nodal metastases in mouse HNSCC.", "[58] SHH medulloblastoma studies identified OLIG2 progenitors that changed to quiescent stem-like states; depletion/deletion impeded initiation and pathway combinations arrested growth.", "[61] In engineered BCC models, Lgr5-positive persisters drove regrowth after vismodegib withdrawal; combined treatment removed most lesions and dual Wnt/Hedgehog inhibition prevented recurrence over the tested four-week follow-up.", "[62] Autochthonous lung tumour reporters, tracing and two ablation approaches showed a high-plasticity hub driving progression, burden and resistant states.", "[63] Patient-derived CRC models showed context-dependent TROP2-positive stemness, chemotherapy-induced state redistribution and enhanced efficacy of combination TROP2-directed treatment.", "[67] Time-resolved colon xenograft clones linked functional stemness to edge location and fibroblast-derived osteopontin, including after chemotherapy.", "[68] Sox2 deletion reduced chemical skin tumour formation; lineage ablation and conditional deletion in established papillomas/SCCs caused regression." ], "what_would_cross_it": "" }, { "subclaim_id": "SC2", "threshold": "Ε", "requirement_quoted": "Requires context-specific causal validity with explicit limits. Cancer stem cells often belong here when a stem-like hierarchy exists in some tumor contexts but fails as a universal model.", "satisfied": "yes", "supporting_evidence": [ "[15] Lentiviral tracking within genetically stable colorectal clones revealed variable propagation and chemotherapy-selected minor or dormant lineages.", "[16] Endogenous multicolour lineage retracing showed Lgr5-positive adenoma cells self-renewing and producing the other adenoma cell types.", "[17] Genetic clonal tracing in native skin tumours distinguished persistent stem-like and transient compartments in papillomas, with different dynamics in invasive carcinoma.", "[18] Pulse-chase and transgene-directed ablation identified an endogenous glioma subset sustaining regrowth after temozolomide; chronic ganciclovir arrested growth and combination treatment impeded development.", "[19] Human CRC organoid lineage tracing and selective LGR5 ablation caused regression followed by regrowth involving KRT20-lineage conversion into LGR5-positive cells.", "[20] Selective Lgr5 ablation restricted primary CRC growth without regression while negative cells replenished the pool; liver metastases showed stronger Lgr5 dependence.", "[27] Marker-independent in-situ pancreatic clonal tracing found widespread clonogenic potential controlled by fibroblast proximity; stromal Hedgehog inhibition altered growth mode.", "[28] Serial pancreatic xenografts were maintained by successive transiently active initiating clones with little overlap between generations.", "[33] Prom1 lineage tracing and depletion in two intact HCC models linked clonal expansion and dynamic dedifferentiation to tumour growth; depletion impeded growth.", "[34] Integrated SCC lineage/state analyses showed chemotherapy suppressing proliferation and activating plasticity; manipulating differentiation enhanced cell-cycle-inhibitor responses.", "[37] Anti-CD123 treatment reduced human AML xenograft engraftment and established disease burden, impaired secondary transplantation and improved mouse survival.", "[40] Clonal HRAS-mutant skin models and functional pathway tests linked dynamic CSC-stromal signalling, angiogenesis and metabolic signalling to malignant transition.", "[42] Functional miR-126 manipulation regulated primary AML self-renewal, differentiation and quiescence through PI3K/AKT/MTOR-associated signalling in vivo.", "[45] Ly6d genetic perturbation in KRAS-driven pancreatic models affected a persistent gastric-like lineage and delayed tumourigenesis; human expression correlated with prognosis.", "[48] POLR1A-high biosynthetic CRC compartments spanned LGR5-positive and negative cells; genetic population ablation imposed irreversible growth arrest in the reported systems.", "[49] Combined Pten/Tgfbr2 perturbation increased reprogramming, rapid prostate tumour development and early mortality with BMP/stemness-associated signalling.", "[50] ABCB5-enriched melanoma cells showed serial xenograft self-renewal and antibody targeting inhibited established tumour growth.", "[53] ABCB5 blockade altered an IL1/IL8/CXCR1 paracrine circuit, induced differentiation, reversed drug resistance and impaired melanoma growth in vivo.", "[57] Anti-CD276 eliminated stem-enriched SCC cells through CD8-dependent immunity and reduced tumour growth and nodal metastases in mouse HNSCC.", "[58] SHH medulloblastoma studies identified OLIG2 progenitors that changed to quiescent stem-like states; depletion/deletion impeded initiation and pathway combinations arrested growth.", "[61] In engineered BCC models, Lgr5-positive persisters drove regrowth after vismodegib withdrawal; combined treatment removed most lesions and dual Wnt/Hedgehog inhibition prevented recurrence over the tested four-week follow-up.", "[62] Autochthonous lung tumour reporters, tracing and two ablation approaches showed a high-plasticity hub driving progression, burden and resistant states.", "[63] Patient-derived CRC models showed context-dependent TROP2-positive stemness, chemotherapy-induced state redistribution and enhanced efficacy of combination TROP2-directed treatment.", "[67] Time-resolved colon xenograft clones linked functional stemness to edge location and fibroblast-derived osteopontin, including after chemotherapy.", "[68] Sox2 deletion reduced chemical skin tumour formation; lineage ablation and conditional deletion in established papillomas/SCCs caused regression." ], "what_would_cross_it": "" }, { "subclaim_id": "SC2", "threshold": "Ζ", "requirement_quoted": "Requires:\n- Independent causal confirmation across models\n- Reduced viability of major alternatives\n- Relevance beyond one assay class", "satisfied": "no", "supporting_evidence": [ "[15] Lentiviral tracking within genetically stable colorectal clones revealed variable propagation and chemotherapy-selected minor or dormant lineages.", "[16] Endogenous multicolour lineage retracing showed Lgr5-positive adenoma cells self-renewing and producing the other adenoma cell types.", "[17] Genetic clonal tracing in native skin tumours distinguished persistent stem-like and transient compartments in papillomas, with different dynamics in invasive carcinoma.", "[18] Pulse-chase and transgene-directed ablation identified an endogenous glioma subset sustaining regrowth after temozolomide; chronic ganciclovir arrested growth and combination treatment impeded development.", "[19] Human CRC organoid lineage tracing and selective LGR5 ablation caused regression followed by regrowth involving KRT20-lineage conversion into LGR5-positive cells.", "[20] Selective Lgr5 ablation restricted primary CRC growth without regression while negative cells replenished the pool; liver metastases showed stronger Lgr5 dependence.", "[27] Marker-independent in-situ pancreatic clonal tracing found widespread clonogenic potential controlled by fibroblast proximity; stromal Hedgehog inhibition altered growth mode.", "[28] Serial pancreatic xenografts were maintained by successive transiently active initiating clones with little overlap between generations.", "[33] Prom1 lineage tracing and depletion in two intact HCC models linked clonal expansion and dynamic dedifferentiation to tumour growth; depletion impeded growth.", "[34] Integrated SCC lineage/state analyses showed chemotherapy suppressing proliferation and activating plasticity; manipulating differentiation enhanced cell-cycle-inhibitor responses.", "[37] Anti-CD123 treatment reduced human AML xenograft engraftment and established disease burden, impaired secondary transplantation and improved mouse survival.", "[40] Clonal HRAS-mutant skin models and functional pathway tests linked dynamic CSC-stromal signalling, angiogenesis and metabolic signalling to malignant transition.", "[42] Functional miR-126 manipulation regulated primary AML self-renewal, differentiation and quiescence through PI3K/AKT/MTOR-associated signalling in vivo.", "[45] Ly6d genetic perturbation in KRAS-driven pancreatic models affected a persistent gastric-like lineage and delayed tumourigenesis; human expression correlated with prognosis.", "[48] POLR1A-high biosynthetic CRC compartments spanned LGR5-positive and negative cells; genetic population ablation imposed irreversible growth arrest in the reported systems.", "[49] Combined Pten/Tgfbr2 perturbation increased reprogramming, rapid prostate tumour development and early mortality with BMP/stemness-associated signalling.", "[50] ABCB5-enriched melanoma cells showed serial xenograft self-renewal and antibody targeting inhibited established tumour growth.", "[53] ABCB5 blockade altered an IL1/IL8/CXCR1 paracrine circuit, induced differentiation, reversed drug resistance and impaired melanoma growth in vivo.", "[57] Anti-CD276 eliminated stem-enriched SCC cells through CD8-dependent immunity and reduced tumour growth and nodal metastases in mouse HNSCC.", "[58] SHH medulloblastoma studies identified OLIG2 progenitors that changed to quiescent stem-like states; depletion/deletion impeded initiation and pathway combinations arrested growth.", "[61] In engineered BCC models, Lgr5-positive persisters drove regrowth after vismodegib withdrawal; combined treatment removed most lesions and dual Wnt/Hedgehog inhibition prevented recurrence over the tested four-week follow-up.", "[62] Autochthonous lung tumour reporters, tracing and two ablation approaches showed a high-plasticity hub driving progression, burden and resistant states.", "[63] Patient-derived CRC models showed context-dependent TROP2-positive stemness, chemotherapy-induced state redistribution and enhanced efficacy of combination TROP2-directed treatment.", "[67] Time-resolved colon xenograft clones linked functional stemness to edge location and fibroblast-derived osteopontin, including after chemotherapy.", "[68] Sox2 deletion reduced chemical skin tumour formation; lineage ablation and conditional deletion in established papillomas/SCCs caused regression." ], "what_would_cross_it": "Across predefined human tumour classes, selective elimination of the alleged fixed CSC population abolishes maintenance without generalized killing, followed by population-specific rescue and tests of replacement from negative cells." }, { "subclaim_id": "SC3", "threshold": "Δ", "requirement_quoted": "Requires at least one meaningful causal perturbation showing the proposed mechanism contributes to initiation, maintenance, or relapse.", "satisfied": "yes", "supporting_evidence": [ "[14] Paired diagnosis/relapse genetics and xenografts traced resistant origins to either rare primitive LSCs or larger committed-phenotype subclones retaining stemness signatures.", "[15] Lentiviral tracking within genetically stable colorectal clones revealed variable propagation and chemotherapy-selected minor or dormant lineages.", "[18] Pulse-chase and transgene-directed ablation identified an endogenous glioma subset sustaining regrowth after temozolomide; chronic ganciclovir arrested growth and combination treatment impeded development.", "[19] Human CRC organoid lineage tracing and selective LGR5 ablation caused regression followed by regrowth involving KRT20-lineage conversion into LGR5-positive cells.", "[20] Selective Lgr5 ablation restricted primary CRC growth without regression while negative cells replenished the pool; liver metastases showed stronger Lgr5 dependence.", "[23] Mouse CRC and human xenograft tracking showed many disseminating Lgr5-negative cells restoring positive stem-like cells; plasticity supported metastatic outgrowth.", "[24] In orthotopic CRC relapse models, pre-resection EMP1-high ablation prevented recurrence in most mice; post-seeding ablation failed, and pre-resection Lgr5 ablation did not prevent recurrence.", "[25] Mex3a-lineage persisters expanded after chemotherapy and transiently shifted away from the WNT/stem program; deficient cells differentiated and failed to resist treatment.", "[26] Mouse and human neoplasia showed variable conventional/regenerative stem-state admixture that adapted under acute selective pressure and tracked chemoresistance.", "[28] Serial pancreatic xenografts were maintained by successive transiently active initiating clones with little overlap between generations.", "[29] Clonal replica pancreatic xenografts exposed pre-existing genetic and functional diversity with different gemcitabine responses.", "[34] Integrated SCC lineage/state analyses showed chemotherapy suppressing proliferation and activating plasticity; manipulating differentiation enhanced cell-cycle-inhibitor responses.", "[36] TNBC profiling identified FXYD3-positive ancestral/persister-like cells that persisted during neoadjuvant therapy and were sensitive to Na/K-pump inhibitors.", "[37] Anti-CD123 treatment reduced human AML xenograft engraftment and established disease burden, impaired secondary transplantation and improved mouse survival.", "[39] Ovarian PDX tumours retained heterogeneity and clinical response patterns; carboplatin/paclitaxel enriched stem-associated populations without making persisters exclusively those populations.", "[42] Functional miR-126 manipulation regulated primary AML self-renewal, differentiation and quiescence through PI3K/AKT/MTOR-associated signalling in vivo.", "[46] TNBC organoids retained EMT-associated ciliated stem-like survivors after chemotherapy; genetic cilia ablation and inhibitors suppressed resistance.", "[47] GATA6 loss in orthotopic CRC organoid models increased metastatic plasticity and LGR5-negative states with little primary-growth change.", "[51] FAK inhibition depleted a transient neural-crest-like residual melanoma state and delayed xenograft relapse, with escape favouring genetic resistance.", "[53] ABCB5 blockade altered an IL1/IL8/CXCR1 paracrine circuit, induced differentiation, reversed drug resistance and impaired melanoma growth in vivo.", "[56] Intravital human CRC organoid xenograft tracing linked pre-existing LGR5/p27 dormancy to survival and post-chemotherapy expansion; COL17A1 loss and YAP interference altered sensitivity/regrowth.", "[57] Anti-CD276 eliminated stem-enriched SCC cells through CD8-dependent immunity and reduced tumour growth and nodal metastases in mouse HNSCC.", "[58] SHH medulloblastoma studies identified OLIG2 progenitors that changed to quiescent stem-like states; depletion/deletion impeded initiation and pathway combinations arrested growth.", "[60] A syngeneic orthotopic intestinal organoid model identified quiescent p57-positive lineages surviving chemotherapy; their ablation suppressed post-treatment regrowth.", "[61] In engineered BCC models, Lgr5-positive persisters drove regrowth after vismodegib withdrawal; combined treatment removed most lesions and dual Wnt/Hedgehog inhibition prevented recurrence over the tested four-week follow-up.", "[62] Autochthonous lung tumour reporters, tracing and two ablation approaches showed a high-plasticity hub driving progression, burden and resistant states.", "[63] Patient-derived CRC models showed context-dependent TROP2-positive stemness, chemotherapy-induced state redistribution and enhanced efficacy of combination TROP2-directed treatment.", "[64] ZFP36L2 loss impaired canonical LGR5 re-entry/metastatic growth while promoting alternative heterogeneous fates; mouse regeneration tests also implicated stress-responsive dedifferentiation.", "[67] Time-resolved colon xenograft clones linked functional stemness to edge location and fibroblast-derived osteopontin, including after chemotherapy." ], "what_would_cross_it": "" }, { "subclaim_id": "SC3", "threshold": "Ε", "requirement_quoted": "Requires context-specific causal validity with explicit limits. Cancer stem cells often belong here when a stem-like hierarchy exists in some tumor contexts but fails as a universal model.", "satisfied": "yes", "supporting_evidence": [ "[14] Paired diagnosis/relapse genetics and xenografts traced resistant origins to either rare primitive LSCs or larger committed-phenotype subclones retaining stemness signatures.", "[15] Lentiviral tracking within genetically stable colorectal clones revealed variable propagation and chemotherapy-selected minor or dormant lineages.", "[18] Pulse-chase and transgene-directed ablation identified an endogenous glioma subset sustaining regrowth after temozolomide; chronic ganciclovir arrested growth and combination treatment impeded development.", "[19] Human CRC organoid lineage tracing and selective LGR5 ablation caused regression followed by regrowth involving KRT20-lineage conversion into LGR5-positive cells.", "[20] Selective Lgr5 ablation restricted primary CRC growth without regression while negative cells replenished the pool; liver metastases showed stronger Lgr5 dependence.", "[23] Mouse CRC and human xenograft tracking showed many disseminating Lgr5-negative cells restoring positive stem-like cells; plasticity supported metastatic outgrowth.", "[24] In orthotopic CRC relapse models, pre-resection EMP1-high ablation prevented recurrence in most mice; post-seeding ablation failed, and pre-resection Lgr5 ablation did not prevent recurrence.", "[25] Mex3a-lineage persisters expanded after chemotherapy and transiently shifted away from the WNT/stem program; deficient cells differentiated and failed to resist treatment.", "[26] Mouse and human neoplasia showed variable conventional/regenerative stem-state admixture that adapted under acute selective pressure and tracked chemoresistance.", "[28] Serial pancreatic xenografts were maintained by successive transiently active initiating clones with little overlap between generations.", "[29] Clonal replica pancreatic xenografts exposed pre-existing genetic and functional diversity with different gemcitabine responses.", "[34] Integrated SCC lineage/state analyses showed chemotherapy suppressing proliferation and activating plasticity; manipulating differentiation enhanced cell-cycle-inhibitor responses.", "[36] TNBC profiling identified FXYD3-positive ancestral/persister-like cells that persisted during neoadjuvant therapy and were sensitive to Na/K-pump inhibitors.", "[37] Anti-CD123 treatment reduced human AML xenograft engraftment and established disease burden, impaired secondary transplantation and improved mouse survival.", "[39] Ovarian PDX tumours retained heterogeneity and clinical response patterns; carboplatin/paclitaxel enriched stem-associated populations without making persisters exclusively those populations.", "[42] Functional miR-126 manipulation regulated primary AML self-renewal, differentiation and quiescence through PI3K/AKT/MTOR-associated signalling in vivo.", "[46] TNBC organoids retained EMT-associated ciliated stem-like survivors after chemotherapy; genetic cilia ablation and inhibitors suppressed resistance.", "[47] GATA6 loss in orthotopic CRC organoid models increased metastatic plasticity and LGR5-negative states with little primary-growth change.", "[51] FAK inhibition depleted a transient neural-crest-like residual melanoma state and delayed xenograft relapse, with escape favouring genetic resistance.", "[53] ABCB5 blockade altered an IL1/IL8/CXCR1 paracrine circuit, induced differentiation, reversed drug resistance and impaired melanoma growth in vivo.", "[56] Intravital human CRC organoid xenograft tracing linked pre-existing LGR5/p27 dormancy to survival and post-chemotherapy expansion; COL17A1 loss and YAP interference altered sensitivity/regrowth.", "[57] Anti-CD276 eliminated stem-enriched SCC cells through CD8-dependent immunity and reduced tumour growth and nodal metastases in mouse HNSCC.", "[58] SHH medulloblastoma studies identified OLIG2 progenitors that changed to quiescent stem-like states; depletion/deletion impeded initiation and pathway combinations arrested growth.", "[60] A syngeneic orthotopic intestinal organoid model identified quiescent p57-positive lineages surviving chemotherapy; their ablation suppressed post-treatment regrowth.", "[61] In engineered BCC models, Lgr5-positive persisters drove regrowth after vismodegib withdrawal; combined treatment removed most lesions and dual Wnt/Hedgehog inhibition prevented recurrence over the tested four-week follow-up.", "[62] Autochthonous lung tumour reporters, tracing and two ablation approaches showed a high-plasticity hub driving progression, burden and resistant states.", "[63] Patient-derived CRC models showed context-dependent TROP2-positive stemness, chemotherapy-induced state redistribution and enhanced efficacy of combination TROP2-directed treatment.", "[64] ZFP36L2 loss impaired canonical LGR5 re-entry/metastatic growth while promoting alternative heterogeneous fates; mouse regeneration tests also implicated stress-responsive dedifferentiation.", "[67] Time-resolved colon xenograft clones linked functional stemness to edge location and fibroblast-derived osteopontin, including after chemotherapy." ], "what_would_cross_it": "" }, { "subclaim_id": "SC3", "threshold": "Ζ", "requirement_quoted": "Requires:\n- Independent causal confirmation across models\n- Reduced viability of major alternatives\n- Relevance beyond one assay class", "satisfied": "no", "supporting_evidence": [ "[14] Paired diagnosis/relapse genetics and xenografts traced resistant origins to either rare primitive LSCs or larger committed-phenotype subclones retaining stemness signatures.", "[15] Lentiviral tracking within genetically stable colorectal clones revealed variable propagation and chemotherapy-selected minor or dormant lineages.", "[18] Pulse-chase and transgene-directed ablation identified an endogenous glioma subset sustaining regrowth after temozolomide; chronic ganciclovir arrested growth and combination treatment impeded development.", "[19] Human CRC organoid lineage tracing and selective LGR5 ablation caused regression followed by regrowth involving KRT20-lineage conversion into LGR5-positive cells.", "[20] Selective Lgr5 ablation restricted primary CRC growth without regression while negative cells replenished the pool; liver metastases showed stronger Lgr5 dependence.", "[23] Mouse CRC and human xenograft tracking showed many disseminating Lgr5-negative cells restoring positive stem-like cells; plasticity supported metastatic outgrowth.", "[24] In orthotopic CRC relapse models, pre-resection EMP1-high ablation prevented recurrence in most mice; post-seeding ablation failed, and pre-resection Lgr5 ablation did not prevent recurrence.", "[25] Mex3a-lineage persisters expanded after chemotherapy and transiently shifted away from the WNT/stem program; deficient cells differentiated and failed to resist treatment.", "[26] Mouse and human neoplasia showed variable conventional/regenerative stem-state admixture that adapted under acute selective pressure and tracked chemoresistance.", "[28] Serial pancreatic xenografts were maintained by successive transiently active initiating clones with little overlap between generations.", "[29] Clonal replica pancreatic xenografts exposed pre-existing genetic and functional diversity with different gemcitabine responses.", "[34] Integrated SCC lineage/state analyses showed chemotherapy suppressing proliferation and activating plasticity; manipulating differentiation enhanced cell-cycle-inhibitor responses.", "[36] TNBC profiling identified FXYD3-positive ancestral/persister-like cells that persisted during neoadjuvant therapy and were sensitive to Na/K-pump inhibitors.", "[37] Anti-CD123 treatment reduced human AML xenograft engraftment and established disease burden, impaired secondary transplantation and improved mouse survival.", "[39] Ovarian PDX tumours retained heterogeneity and clinical response patterns; carboplatin/paclitaxel enriched stem-associated populations without making persisters exclusively those populations.", "[42] Functional miR-126 manipulation regulated primary AML self-renewal, differentiation and quiescence through PI3K/AKT/MTOR-associated signalling in vivo.", "[46] TNBC organoids retained EMT-associated ciliated stem-like survivors after chemotherapy; genetic cilia ablation and inhibitors suppressed resistance.", "[47] GATA6 loss in orthotopic CRC organoid models increased metastatic plasticity and LGR5-negative states with little primary-growth change.", "[51] FAK inhibition depleted a transient neural-crest-like residual melanoma state and delayed xenograft relapse, with escape favouring genetic resistance.", "[53] ABCB5 blockade altered an IL1/IL8/CXCR1 paracrine circuit, induced differentiation, reversed drug resistance and impaired melanoma growth in vivo.", "[56] Intravital human CRC organoid xenograft tracing linked pre-existing LGR5/p27 dormancy to survival and post-chemotherapy expansion; COL17A1 loss and YAP interference altered sensitivity/regrowth.", "[57] Anti-CD276 eliminated stem-enriched SCC cells through CD8-dependent immunity and reduced tumour growth and nodal metastases in mouse HNSCC.", "[58] SHH medulloblastoma studies identified OLIG2 progenitors that changed to quiescent stem-like states; depletion/deletion impeded initiation and pathway combinations arrested growth.", "[60] A syngeneic orthotopic intestinal organoid model identified quiescent p57-positive lineages surviving chemotherapy; their ablation suppressed post-treatment regrowth.", "[61] In engineered BCC models, Lgr5-positive persisters drove regrowth after vismodegib withdrawal; combined treatment removed most lesions and dual Wnt/Hedgehog inhibition prevented recurrence over the tested four-week follow-up.", "[62] Autochthonous lung tumour reporters, tracing and two ablation approaches showed a high-plasticity hub driving progression, burden and resistant states.", "[63] Patient-derived CRC models showed context-dependent TROP2-positive stemness, chemotherapy-induced state redistribution and enhanced efficacy of combination TROP2-directed treatment.", "[64] ZFP36L2 loss impaired canonical LGR5 re-entry/metastatic growth while promoting alternative heterogeneous fates; mouse regeneration tests also implicated stress-responsive dedifferentiation.", "[67] Time-resolved colon xenograft clones linked functional stemness to edge location and fibroblast-derived osteopontin, including after chemotherapy." ], "what_would_cross_it": "Prospective state/clone tracing plus state-specific targeting improves durable relapse-free survival over matched bulk killing, with pre-existing versus induced states distinguished." }, { "subclaim_id": "SC4", "threshold": "Δ", "requirement_quoted": "Requires at least one meaningful causal perturbation showing the proposed mechanism contributes to initiation, maintenance, or relapse.", "satisfied": "no", "supporting_evidence": [ "[6] More permissive host conditions detected tumour formation from many unselected human melanoma cells, including single-cell inocula.", "[7] Single-cell melanoma transplants revealed multiple propagating phenotypes with different capacities to reconstruct heterogeneity and resist chemotherapy.", "[8] Inducing EMT in mammary epithelial systems increased stem-associated properties and tumour-forming activity after transformation.", "[9] Purified mammary non-stem populations spontaneously generated stem-like cells, with enhanced conversion after transformation in vitro and in vivo.", "[10] Sorted breast cancer cell-line states returned toward equilibrium proportions, consistent with stochastic transitions and de novo stem-like states.", "[14] Paired diagnosis/relapse genetics and xenografts traced resistant origins to either rare primitive LSCs or larger committed-phenotype subclones retaining stemness signatures.", "[15] Lentiviral tracking within genetically stable colorectal clones revealed variable propagation and chemotherapy-selected minor or dormant lineages.", "[17] Genetic clonal tracing in native skin tumours distinguished persistent stem-like and transient compartments in papillomas, with different dynamics in invasive carcinoma.", "[19] Human CRC organoid lineage tracing and selective LGR5 ablation caused regression followed by regrowth involving KRT20-lineage conversion into LGR5-positive cells.", "[20] Selective Lgr5 ablation restricted primary CRC growth without regression while negative cells replenished the pool; liver metastases showed stronger Lgr5 dependence.", "[21] Edited patient-derived CRC organoid xenografts showed long-term LGR5-lineage self-renewal and differentiated descendants.", "[22] CRC cells downregulated initiating-cell markers under differentiating adherent conditions yet retained serial xenograft tumour initiation and clonal contribution.", "[23] Mouse CRC and human xenograft tracking showed many disseminating Lgr5-negative cells restoring positive stem-like cells; plasticity supported metastatic outgrowth.", "[24] In orthotopic CRC relapse models, pre-resection EMP1-high ablation prevented recurrence in most mice; post-seeding ablation failed, and pre-resection Lgr5 ablation did not prevent recurrence.", "[25] Mex3a-lineage persisters expanded after chemotherapy and transiently shifted away from the WNT/stem program; deficient cells differentiated and failed to resist treatment.", "[26] Mouse and human neoplasia showed variable conventional/regenerative stem-state admixture that adapted under acute selective pressure and tracked chemoresistance.", "[27] Marker-independent in-situ pancreatic clonal tracing found widespread clonogenic potential controlled by fibroblast proximity; stromal Hedgehog inhibition altered growth mode.", "[28] Serial pancreatic xenografts were maintained by successive transiently active initiating clones with little overlap between generations.", "[29] Clonal replica pancreatic xenografts exposed pre-existing genetic and functional diversity with different gemcitabine responses.", "[32] Pre/post-mutation STRACK tracing showed driver-specific expansion of differentiation-primed stem cells and Npm1c-associated reversal toward primitive malignant states.", "[33] Prom1 lineage tracing and depletion in two intact HCC models linked clonal expansion and dynamic dedifferentiation to tumour growth; depletion impeded growth.", "[34] Integrated SCC lineage/state analyses showed chemotherapy suppressing proliferation and activating plasticity; manipulating differentiation enhanced cell-cycle-inhibitor responses.", "[36] TNBC profiling identified FXYD3-positive ancestral/persister-like cells that persisted during neoadjuvant therapy and were sensitive to Na/K-pump inhibitors.", "[38] Perturbing endogenous PU.1 or withdrawing differentiation treatment allowed mature AML cells in murine and human models to regain clonogenic/leukemogenic activity.", "[39] Ovarian PDX tumours retained heterogeneity and clinical response patterns; carboplatin/paclitaxel enriched stem-associated populations without making persisters exclusively those populations.", "[40] Clonal HRAS-mutant skin models and functional pathway tests linked dynamic CSC-stromal signalling, angiogenesis and metabolic signalling to malignant transition.", "[43] Barcoded primary ALL blasts showed many approximately equipotent founders contributing through serial transplants rather than a rare dominant apex.", "[44] Prostate small-cell PDXs expressed reprogramming factors, and factor transfection altered expression and stem-like colony phenotypes.", "[45] Ly6d genetic perturbation in KRAS-driven pancreatic models affected a persistent gastric-like lineage and delayed tumourigenesis; human expression correlated with prognosis.", "[46] TNBC organoids retained EMT-associated ciliated stem-like survivors after chemotherapy; genetic cilia ablation and inhibitors suppressed resistance.", "[47] GATA6 loss in orthotopic CRC organoid models increased metastatic plasticity and LGR5-negative states with little primary-growth change.", "[48] POLR1A-high biosynthetic CRC compartments spanned LGR5-positive and negative cells; genetic population ablation imposed irreversible growth arrest in the reported systems.", "[49] Combined Pten/Tgfbr2 perturbation increased reprogramming, rapid prostate tumour development and early mortality with BMP/stemness-associated signalling.", "[51] FAK inhibition depleted a transient neural-crest-like residual melanoma state and delayed xenograft relapse, with escape favouring genetic resistance.", "[52] Marker-sorted melanoma populations transiently overshot stem-marker equilibrium, consistent with regulated phenotypic switching after depletion.", "[53] ABCB5 blockade altered an IL1/IL8/CXCR1 paracrine circuit, induced differentiation, reversed drug resistance and impaired melanoma growth in vivo.", "[54] Chronic extracellular acidosis increased melanoma stem-associated and tumour-initiating properties, with a reversible phenotype linked to EMT.", "[55] Reporter-tracked human intestinal tumour organoids showed lactate suppressing differentiation and inducing a proliferative stem state through acetylation/MYC-associated regulation.", "[56] Intravital human CRC organoid xenograft tracing linked pre-existing LGR5/p27 dormancy to survival and post-chemotherapy expansion; COL17A1 loss and YAP interference altered sensitivity/regrowth.", "[58] SHH medulloblastoma studies identified OLIG2 progenitors that changed to quiescent stem-like states; depletion/deletion impeded initiation and pathway combinations arrested growth.", "[59] Direct patient melanoma cells frequently initiated serially transplantable tumours in permissive hosts; diverse markers failed to separate a large non-tumorigenic compartment and were reversible.", "[60] A syngeneic orthotopic intestinal organoid model identified quiescent p57-positive lineages surviving chemotherapy; their ablation suppressed post-treatment regrowth.", "[62] Autochthonous lung tumour reporters, tracing and two ablation approaches showed a high-plasticity hub driving progression, burden and resistant states.", "[63] Patient-derived CRC models showed context-dependent TROP2-positive stemness, chemotherapy-induced state redistribution and enhanced efficacy of combination TROP2-directed treatment.", "[64] ZFP36L2 loss impaired canonical LGR5 re-entry/metastatic growth while promoting alternative heterogeneous fates; mouse regeneration tests also implicated stress-responsive dedifferentiation.", "[65] Intravital lineage tracing in unperturbed mammary tumours documented disappearance of existing stem-like contributors and formation of new ones.", "[66] GBM stem-marker populations exhibited reversible microenvironment-instructed transitions; faster reconstitution of heterogeneity conferred an in-vivo growth advantage.", "[67] Time-resolved colon xenograft clones linked functional stemness to edge location and fibroblast-derived osteopontin, including after chemotherapy." ], "what_would_cross_it": "Bidirectional native fate mapping under baseline and treatment, with adequate detection limits, demonstrates irreversible membership and excludes state regeneration across the registered settings." }, { "subclaim_id": "SC5", "threshold": "Δ", "requirement_quoted": "Requires at least one meaningful causal perturbation showing the proposed mechanism contributes to initiation, maintenance, or relapse.", "satisfied": "no", "supporting_evidence": [ "[6] More permissive host conditions detected tumour formation from many unselected human melanoma cells, including single-cell inocula.", "[7] Single-cell melanoma transplants revealed multiple propagating phenotypes with different capacities to reconstruct heterogeneity and resist chemotherapy.", "[14] Paired diagnosis/relapse genetics and xenografts traced resistant origins to either rare primitive LSCs or larger committed-phenotype subclones retaining stemness signatures.", "[20] Selective Lgr5 ablation restricted primary CRC growth without regression while negative cells replenished the pool; liver metastases showed stronger Lgr5 dependence.", "[27] Marker-independent in-situ pancreatic clonal tracing found widespread clonogenic potential controlled by fibroblast proximity; stromal Hedgehog inhibition altered growth mode.", "[38] Perturbing endogenous PU.1 or withdrawing differentiation treatment allowed mature AML cells in murine and human models to regain clonogenic/leukemogenic activity.", "[43] Barcoded primary ALL blasts showed many approximately equipotent founders contributing through serial transplants rather than a rare dominant apex.", "[50] ABCB5-enriched melanoma cells showed serial xenograft self-renewal and antibody targeting inhibited established tumour growth.", "[59] Direct patient melanoma cells frequently initiated serially transplantable tumours in permissive hosts; diverse markers failed to separate a large non-tumorigenic compartment and were reversible." ], "what_would_cross_it": "An independently replicated cross-histology causal dependency series satisfies stable membership, necessity for maintenance and durable relapse, and matched rescue in human disease or convergent field-valid equivalents." } ], "generalization_check": { "generalization_tested": "yes", "context_boundary_mapped": "yes", "internal_negative_controls": [ "HPCS-versus-random and AT1-like tracing/ablation controls; incomplete reporter recombination explicitly detected.", "EMP1 pre-resection versus post-seeding ablation and independent Lgr5 ablation constructs; nude hosts reduce adaptive-immunity confounding.", "TROP2 targeted versus same-payload untargeted ADC and normal-tissue organoids; treatment/washout state recovery.", "BCC Wnt monotherapy, combined therapy and short withdrawal follow-up; normal liver toxicity limits sustained ablation." ], "note": "Dependency varies by histology, genotype, primary versus metastasis, treatment timing, observation horizon and assay host. These variables are prespecified scope limits, not post-hoc responder exclusions. Human-origin organoid/xenograft results do not become native human causal proof. Shared cohorts were not inferred absent merely because names differed." }, "falsification_patterns_met": [ { "pattern": "Proposed CSC fraction is not required for maintenance/relapse", "evidence": "Lgr5-negative cells maintain primary CRC; pre-resection Lgr5 depletion in EMP1 relapse models fails to prevent recurrence.", "downgrade_applied": false, "note": "Already determines the SC5 threshold stop; no second numerical penalty." }, { "pattern": "Non-CSC populations reacquire equivalent function robustly", "evidence": "KRT20 CRC reversion, mature AML dedifferentiation, mammary contributor turnover and non-HPCS re-entry.", "downgrade_applied": false, "note": "Already incorporated in SC4/SC5; does not refute context-specific state dependency." } ], "pitfalls_flagged": [ { "pitfall": "Marker identity confused with function", "where": "CD133/CD44/ABCB5/LGR5 sorting and transcriptomic stemness programs." }, { "pitfall": "Xenograft capacity equated with endogenous hierarchy", "where": "Historical solid-tumour initiation assays and engineered human organoid hosts." }, { "pitfall": "Relapse association mistaken for relapse causation", "where": "Patient survival signatures and persistent marker enrichment." }, { "pitfall": "Plasticity ignored", "where": "Negative-to-positive reconstitution and therapy-induced TROP2/HPCS states." }, { "pitfall": "Broad generalization across tumor types", "where": "Fixed necessary apex extrapolated from one tissue or treatment phase." } ], "causal_tally_audit": { "tally_claimed_by_document": 56, "tally_after_audit": 56, "items_rejected": [ "Null and negative contrasts are discriminators, not positive threshold crossings. Reports and replications are not independent causal lines.", "Selective killing of a state can affect multiple functions; it is not identical to a mechanism-specific rescue.", "Prevention over a short mouse follow-up is not durable clinical cure.", "Null/contrary perturbations and fate tests are discriminators but not positive universal threshold crossings." ] }, "steelman": { "case_one_rung_higher": "One rung higher, Δ, is compelling if the claim is read as stem-like states contributing to cancer behaviour: several native ablations exceed that boundary. For the registered SC5 fixed cross-human necessity gate, Δ would require that the same fixed-population mechanism actually passes a relevant broad-scope dependency test; present successes and replacement failures do not supply it.", "case_one_rung_lower": "One rung lower, Β, would fit expression/prognosis alone. It is rejected because native tracing, precise ablation, patient-origin functional studies and state reversal supply substantially more than association. Γ is not assigned by ignoring these sources.", "which_rejected": "Reject Β for undercrediting native causal studies and reject global Δ because it silently weakens the fixed cross-human claim. Preserve Ζ existence and Ε context-specific maintenance/relapse, while the exact nominal gate remains Γ.", "blocking_cap_threshold_or_missing_experiment": "Missing experiment: In prespecified AML and epithelial tumour cohorts, combine longitudinal clone/state tracking with selective depletion of the putative stable apex, an equally cytotoxic bulk-killing comparator and population-specific rescue; quantify replacement from negative states and durable maintenance/relapse. Use native human serial sampling and independent disease-relevant perturbation platforms rather than relying on one marker or host." }, "final_score": { "hsef_level": "Γ", "hsef_descriptor": "Mechanistically plausible, partial system support", "confidence": "Moderate", "confidence_rationale": "68 primary reports with 5 selected partial-body examinations; density, heterogeneous controls and incomplete access set the confidence, not correctness.", "rests_on_non_peer_reviewed_work": false, "rationale": "Γ for the exact registered broad fixed-hierarchy claim. The cancer rubric explicitly permits Ε for context-specific CSC validity; that threshold is awarded to SC2 and SC3 rather than silently replacing SC5 with a weaker functional-stemness statement. Across-context causal studies are credited as a convergent set, but their results include genuine population replacement, stage-specific dispensability and alternative lineage routes. They therefore do not cross the fixed cross-human necessity gate. Scope-matched and primary-subclaim aggregation both return Γ; weakest-link also returns Γ. Narrow existence is Ζ, and defined maintenance/relapse dependencies are Ε." }, "role_of_mechanism": { "classification": "reinforcing / stabilizing factor", "derivation_step_matched": 5, "derivation": "Step1: tumour-generated stress/niches can induce stem states, but those states feed back on growth; the complete mechanism is not solely a downstream consequence. Step2: ablation and functional state tests establish dependency in some contexts, excluding mere co-occurrence. Step3: no universal initiation-plus-removal-plus-rate-limiting case for the fixed hierarchy. Step4: universal irreplaceable membership is contradicted by recovery and alternate states. Step5 therefore applies to the registered broad mechanism: stem-like functions reinforce/maintain malignancy initiated by upstream events, with permissive or stronger dependencies in explicitly bounded settings.", "tournament_used_as_tiebreaker": false, "note": "Derived from causal direction, not tournament rank." }, "extended_scoring_MSD": { "momentum": { "value": "Mechanistic only", "artifact": "The 2026 HPCS, TROP2 and ZFP36L2 programmes test causal state plasticity and therapeutic vulnerabilities. They do not constitute a verified current cross-human fixed-population necessity programme; no ongoing/recruiting clinical trial status is asserted.", "justification": "The 2026 HPCS, TROP2 and ZFP36L2 programmes test causal state plasticity and therapeutic vulnerabilities. They do not constitute a verified current cross-human fixed-population necessity programme; no ongoing/recruiting clinical trial status is asserted." }, "stability": { "value": "Stable", "trigger": "No verified pending result matching fixed membership and cross-human necessary maintenance/relapse is identified; the already published 2026 findings are included rather than treated as future triggers.", "justification": "No verified pending result matching fixed membership and cross-human necessary maintenance/relapse is identified; the already published 2026 findings are included rather than treated as future triggers." }, "divergence": { "implied_level": null, "implied_level_basis": "No single field-implied level is defensible from conflicting framings.", "assessed_level": "Γ", "gap_in_rungs": null, "value": "Contested", "justification": "No manufactured field consensus or arithmetic gap." }, "calibration_note": "M/S/D never modify HSEF level or confidence." }, "change_record": { "applies": false, "prior_level": "Ranking categorical verdict visible; no prior letter used as a target", "prior_confidence": null, "prior_source": null, "derived_before_consulting_prior": false, "new_level": "Γ", "direction": "newly assigned", "what_moved_it": "Fresh primary evidence appraisal; not blinded.", "divergence_from_other_reviewers": null }, "proposed_decisive_experiments": [ { "name": "Registered boundary experiment", "experiment": "In prespecified AML and epithelial tumour cohorts, combine longitudinal clone/state tracking with selective depletion of the putative stable apex, an equally cytotoxic bulk-killing comparator and population-specific rescue; quantify replacement from negative states and durable maintenance/relapse. Use native human serial sampling and independent disease-relevant perturbation platforms rather than relying on one marker or host.", "readout": "Clone ancestry, bidirectional transition frequencies, target engagement, total burden and durable relapse-free survival with prespecified state-replacement detection limits", "critical_control": "Marker-independent tracking; lineage-label induction controls; intact niche; normal stem-cell toxicity; orthogonal targeting; sham and matched bulk cytotoxicity; blinded relapse assessment; rescue without changing oncogenic drivers", "supporting_result": "Irreplaceable fixed-apex depletion abolishes maintenance and recurrence across predefined classes, with selective rescue restoring both and no regeneration from negative cells", "falsifying_result": "Negative cells or alternate states sustain disease or regenerate the apex; selective depletion fails despite verified engagement, or benefit tracks generalized killing rather than state dependency" } ], "knowledge_gaps": [ { "name": "Gap 1", "statement": "Native human fate and dependency: distinguish engraftment potential from in-patient contribution, using safe serial lineage/genotype/state reconstruction rather than assuming reporter xenografts are native evidence (PMID28355176, PMID28658204, PMID37098346).", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 2", "statement": "Selection versus induction: measure the origin of post-treatment stem states with simultaneous ancestry and state tracking; pseudotime alone cannot determine dedifferentiation (PMID23225641, PMID42386981, PMID40010350).", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 3", "statement": "Ablation-resistant replacement and timing: determine which reservoirs regenerate an apex and when a state becomes dispensable after seeding; prespecify primary, micrometastatic and established-metastatic phases (PMID28358093, PMID36352230, PMID42557330).", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 4", "statement": "Mechanism-specific clinical benefit: establish whether selectively targeting a functional state improves durable survival beyond equivalent bulk cytotoxicity and multicomponent pathway effects (PMID19570512, PMID33945793, PMID42386981).", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 5", "statement": "Normal-tissue therapeutic window and durability: quantify normal stem-cell injury, incomplete targeting, escape and post-withdrawal relapse over longer horizons (PMID30297799, PMID41565826).", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 6", "statement": "Prospective cross-histology predictions: define before observation which genotypes/niches retain a hierarchy, which replenish it and which bypass it; prevent a hybrid model from becoming unfalsifiable (PMID34686335, PMID21075313, PMID41545197).", "relevance": "Limits mechanism identification or scope." } ], "review_metadata": { "review_date": "2026-10-05", "reviewer": "Codex", "evidence_base_note": "68 primary reports; literature cutoff 2026-10-05; source examination UTC date 2026-10-06; bounded critical review, not exhaustive systematic review.", "literature_tools_available": true, "literature_tools_note": "Life Sciences Literature PubMed/Europe PMC; signed-in Consensus browser discovery and attempted indexed full-text extraction. Successful passages and failures are reconciled with original sections where available; see case reconciliation. Zero Consensus API calls.", "skill_version": "5.3", "validator_run": "exact archived v5.3 validator 2.3; see validator.txt", "validator_warnings_addressed": "Phenomenon entry was restated as the preregistered causal claim. No real phenomenon is labelled refuted; warning is explicitly justified.", "consensus_consistency_audit": "2026-10-09; supplementary provenance/source reconciliation; original grading retained; prior grades visible." }, "is_calibration_entry": { "value": false, "entry_role": "not_calibration", "blind_graded": null, "completed_blinded_calibration": false, "expected_band_sealed_at": "", "target_sha256": "", "target_authorship": "not applicable", "target_author_saw_review": null, "future_run_status": "not prepared", "unblinded_reason": "Ranking categorical verdict and index guidance were visible. No completed blinded calibration claimed." }, "upper_ladder_check": { "final_level_below_zeta": true, "equivalents_considered": [ { "kind": "mendelian_randomization", "available": false, "why_not_sufficient": "Withdrawal/rechallenge and combined pathway treatment have tumour-burden/relapse consequences in BCC models, with human biopsy/treatment-withdrawal linkage. Precise native skin/glioma/lung perturbations and patient-origin clone tracking provide upper-ladder-relevant convergence. They earn narrow causal credit, not a cap at association. No examined genetic natural experiment, cross-population dose response, human state-selective durable clinical endpoint or matched restoration establishes the full fixed hierarchy across human cancers. Actual recovery/dispensability observations constrain advancement more than an absence of randomized trials." }, { "kind": "natural_experiment", "available": false, "why_not_sufficient": "Withdrawal/rechallenge and combined pathway treatment have tumour-burden/relapse consequences in BCC models, with human biopsy/treatment-withdrawal linkage. Precise native skin/glioma/lung perturbations and patient-origin clone tracking provide upper-ladder-relevant convergence. They earn narrow causal credit, not a cap at association. No examined genetic natural experiment, cross-population dose response, human state-selective durable clinical endpoint or matched restoration establishes the full fixed hierarchy across human cancers. Actual recovery/dispensability observations constrain advancement more than an absence of randomized trials." }, { "kind": "dose_response_across_populations", "available": false, "why_not_sufficient": "Withdrawal/rechallenge and combined pathway treatment have tumour-burden/relapse consequences in BCC models, with human biopsy/treatment-withdrawal linkage. Precise native skin/glioma/lung perturbations and patient-origin clone tracking provide upper-ladder-relevant convergence. They earn narrow causal credit, not a cap at association. No examined genetic natural experiment, cross-population dose response, human state-selective durable clinical endpoint or matched restoration establishes the full fixed hierarchy across human cancers. Actual recovery/dispensability observations constrain advancement more than an absence of randomized trials." }, { "kind": "withdrawal_rechallenge", "available": true, "why_not_sufficient": "Withdrawal/rechallenge and combined pathway treatment have tumour-burden/relapse consequences in BCC models, with human biopsy/treatment-withdrawal linkage. Precise native skin/glioma/lung perturbations and patient-origin clone tracking provide upper-ladder-relevant convergence. They earn narrow causal credit, not a cap at association. No examined genetic natural experiment, cross-population dose response, human state-selective durable clinical endpoint or matched restoration establishes the full fixed hierarchy across human cancers. Actual recovery/dispensability observations constrain advancement more than an absence of randomized trials." }, { "kind": "therapeutic_perturbation_hard_endpoint", "available": true, "why_not_sufficient": "Withdrawal/rechallenge and combined pathway treatment have tumour-burden/relapse consequences in BCC models, with human biopsy/treatment-withdrawal linkage. Precise native skin/glioma/lung perturbations and patient-origin clone tracking provide upper-ladder-relevant convergence. They earn narrow causal credit, not a cap at association. No examined genetic natural experiment, cross-population dose response, human state-selective durable clinical endpoint or matched restoration establishes the full fixed hierarchy across human cancers. Actual recovery/dispensability observations constrain advancement more than an absence of randomized trials." } ], "convergence_present": true, "cap_reapplied_to_convergent_set": false }, "provenance_header": { "sources_total": 68, "claims_total": 74, "claims_verified": 74, "claims_unverified": 0, "claims_contradicted": 0, "tier_a_sources": 68, "generated_by": "Codex; HSEF v5.3", "gate_passed": true }, "claims": [ { "id": "C1", "text": "Marker-fractionated human AML cells initiated disseminated leukemia in cytokine-treated SCID hosts, defining transplantation-enriched initiating activity. Engraftment selection does not establish an immutable endogenous hierarchy or necessity for maintenance and relapse in patients.", "carries_number": false, "load_bearing_for": [ "SC1", "SC5" ], "source_ns": [ 1 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C2", "text": "Primitive CD34-high CD38-negative fractions from tested AML subtypes self-renewed and generated differentiated leukemic blasts in NOD/SCID mice. Assay-defined exclusivity need not persist with different host permissiveness or show the original patient's tumour maintenance mechanism.", "carries_number": true, "load_bearing_for": [ "SC1", "SC5" ], "source_ns": [ 2 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C3", "text": "Prospectively isolated CD44-positive CD24-low breast tumour cells showed enriched serial tumour formation and regenerated heterogeneity in immunocompromised mice. Selected xenograft initiation in a small patient series is not universal fixed-hierarchy necessity; linked erratum details were not resolved.", "carries_number": true, "load_bearing_for": [ "SC1", "SC5" ], "source_ns": [ 3 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C4", "text": "CD133-positive human brain tumour fractions generated serially transplantable phenocopies at lower inocula than the tested negative fractions. CD133 enrichment in this host assay does not establish permanent marker exclusivity, endogenous maintenance necessity or relapse prevention.", "carries_number": true, "load_bearing_for": [ "SC1", "SC5" ], "source_ns": [ 4 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C5", "text": "Single colon cancer cells self-renewed and generated differentiated tumour progeny after culture and xenotransplantation; PI3K signalling affected lineage decisions. Clonal multilineage potential is compatible with plastic hierarchies and does not prove an irreplaceable fixed population in patients.", "carries_number": true, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 5 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C6", "text": "More permissive host conditions detected tumour formation from many unselected human melanoma cells, including single-cell inocula. High transplantation competence challenges rarity and assay exclusivity but alone does not quantify endogenous fate or refute all functional hierarchies.", "carries_number": false, "load_bearing_for": [ "SC1", "SC4", "SC5" ], "source_ns": [ 6 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C7", "text": "Single-cell melanoma transplants revealed multiple propagating phenotypes with different capacities to reconstruct heterogeneity and resist chemotherapy. Transplanted mouse tumour populations do not establish patient recurrence mechanisms; self-renewal need not require multilineage differentiation.", "carries_number": false, "load_bearing_for": [ "SC1", "SC4", "SC5" ], "source_ns": [ 7 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C8", "text": "Inducing EMT in mammary epithelial systems increased stem-associated properties and tumour-forming activity after transformation. Induced EMT and sphere readouts do not measure natural bidirectional transitions or establish universal therapy-resistant CSC identity.", "carries_number": false, "load_bearing_for": [ "SC4" ], "source_ns": [ 8 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C9", "text": "Purified mammary non-stem populations spontaneously generated stem-like cells, with enhanced conversion after transformation in vitro and in vivo. Selected mammary systems do not establish transition rates across all tumours; spontaneous conversion undermines a permanently one-way hierarchy.", "carries_number": false, "load_bearing_for": [ "SC4" ], "source_ns": [ 9 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C10", "text": "Sorted breast cancer cell-line states returned toward equilibrium proportions, consistent with stochastic transitions and de novo stem-like states. A Markov fit and cultured state recovery do not uniquely identify endogenous patient fate dynamics; two linked errata remain unresolved.", "carries_number": false, "load_bearing_for": [ "SC4" ], "source_ns": [ 10 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C11", "text": "Functionally xenograft-validated human AML stemness programs predicted patient survival, bridging transplantation activity and clinical association. Prognostic prediction is not selective LSC eradication or proof that a fixed population is necessary for relapse.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3", "SC5" ], "source_ns": [ 11 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C12", "text": "DNMT3A-mutant pre-leukemic HSCs lacked later NPM1 lesions, repopulated multilineage xenografts and persisted in remission samples. A pre-leukemic reservoir is not identical to the overt AML-maintaining population; presence after chemotherapy does not prove inevitable relapse.", "carries_number": true, "load_bearing_for": [ "SC3", "SC4" ], "source_ns": [ 12 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C13", "text": "Single-cell genotyping and transcriptional profiling mapped variable malignant differentiation spectra across AML patients and subclones. Expression-defined primitive states and prognosis do not by themselves establish lineage direction, necessity or a stable universal hierarchy.", "carries_number": false, "load_bearing_for": [ "SC1", "SC4", "SC5" ], "source_ns": [ 13 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C14", "text": "Paired diagnosis/relapse genetics and xenografts traced resistant origins to either rare primitive LSCs or larger committed-phenotype subclones retaining stemness signatures. The two relapse patterns support functional stemness while contradicting a universal rare primitive phenotype; no randomized selective patient LSC ablation was tested.", "carries_number": false, "load_bearing_for": [ "SC3", "SC4", "SC5" ], "source_ns": [ 14 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C15", "text": "Lentiviral tracking within genetically stable colorectal clones revealed variable propagation and chemotherapy-selected minor or dormant lineages. Serial xenografts select engraftment-capable cells and do not distinguish every source of state variability in untreated patients.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3", "SC4" ], "source_ns": [ 15 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C16", "text": "Endogenous multicolour lineage retracing showed Lgr5-positive adenoma cells self-renewing and producing the other adenoma cell types. A lineage contribution in mouse precursor adenomas is not necessity, patient carcinoma relapse, or proof that negative cells cannot regenerate stemness.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 16 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C17", "text": "Genetic clonal tracing in native skin tumours distinguished persistent stem-like and transient compartments in papillomas, with different dynamics in invasive carcinoma. Contribution and stage-dependent clonal behaviour do not prove universal rare-CSC necessity or an invariant hierarchy through progression.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2", "SC4" ], "source_ns": [ 17 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C18", "text": "Pulse-chase and transgene-directed ablation identified an endogenous glioma subset sustaining regrowth after temozolomide; chronic ganciclovir arrested growth and combination treatment impeded development. The engineered glioma and nestin-TK targeting define a context-specific dependency, not universal patient CSC identity or selective clinical relapse prevention.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 18 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C19", "text": "Human CRC organoid lineage tracing and selective LGR5 ablation caused regression followed by regrowth involving KRT20-lineage conversion into LGR5-positive cells. Engineered organoid xenografts show a plastic functional hierarchy rather than necessity of a permanently distinct pre-existing CSC population in patients.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2", "SC3", "SC4" ], "source_ns": [ 19 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C20", "text": "Selective Lgr5 ablation restricted primary CRC growth without regression while negative cells replenished the pool; liver metastases showed stronger Lgr5 dependence. Dependency differs by anatomical stage; primary maintenance despite ablation contradicts universal fixed-population necessity while preserving a metastatic dependency.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3", "SC4", "SC5" ], "source_ns": [ 20 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C21", "text": "Edited patient-derived CRC organoid xenografts showed long-term LGR5-lineage self-renewal and differentiated descendants. Human-origin material in an engineered mouse host is not intact-patient fate tracing, and lineage contribution alone does not demonstrate necessity.", "carries_number": true, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 21 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C22", "text": "CRC cells downregulated initiating-cell markers under differentiating adherent conditions yet retained serial xenograft tumour initiation and clonal contribution. Culture-induced marker differentiation does not identify every endogenous transition, but marker-defined phenotype was not necessary for transplantation activity.", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 22 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C23", "text": "Mouse CRC and human xenograft tracking showed many disseminating Lgr5-negative cells restoring positive stem-like cells; plasticity supported metastatic outgrowth. Seeding, establishment and outgrowth are distinct phases; a plastic stem state requirement is not a fixed originating cell population requirement.", "carries_number": true, "load_bearing_for": [ "SC3", "SC4" ], "source_ns": [ 23 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C24", "text": "In orthotopic CRC relapse models, pre-resection EMP1-high ablation prevented recurrence in most mice; post-seeding ablation failed, and pre-resection Lgr5 ablation did not prevent recurrence. Timing and metastatic stage determine dependency; patient signatures were associative, and EMP1 residual states are not an immutable LGR5 apex.", "carries_number": true, "load_bearing_for": [ "SC3", "SC4" ], "source_ns": [ 24 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 5:Relapse by residual EMP1+ cells. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C25", "text": "Mex3a-lineage persisters expanded after chemotherapy and transiently shifted away from the WNT/stem program; deficient cells differentiated and failed to resist treatment. A therapy-dependent, niche-adaptive persister state is not an invariant CSC phenotype; clinical selective targeting and durable patient relapse prevention were not tested.", "carries_number": true, "load_bearing_for": [ "SC3", "SC4" ], "source_ns": [ 25 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C26", "text": "Mouse and human neoplasia showed variable conventional/regenerative stem-state admixture that adapted under acute selective pressure and tracked chemoresistance. The fitness-landscape interpretation is not a unique proof of transition causation; a linked corrigendum remains part of the access limit.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3", "SC4" ], "source_ns": [ 26 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C27", "text": "Marker-independent in-situ pancreatic clonal tracing found widespread clonogenic potential controlled by fibroblast proximity; stromal Hedgehog inhibition altered growth mode. Spatially instructed clonogenicity challenges a fixed rare apex, but the perturbation can change multiple stromal functions and does not cover every PDAC subtype.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2", "SC4", "SC5" ], "source_ns": [ 27 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C28", "text": "Serial pancreatic xenografts were maintained by successive transiently active initiating clones with little overlap between generations. Transplant bottlenecks may contribute to clonal succession; these data challenge fixed continual activity without establishing native patient dynamics.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3", "SC4" ], "source_ns": [ 28 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C29", "text": "Clonal replica pancreatic xenografts exposed pre-existing genetic and functional diversity with different gemcitabine responses. Drug sensitivity and predictive signatures do not show that one stable CSC compartment is necessary for patient relapse.", "carries_number": false, "load_bearing_for": [ "SC3", "SC4" ], "source_ns": [ 29 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C30", "text": "Single-cell sequencing of AML marrow resolved progenitor states and associations between ribosomal programs, subtype and remission. A transcriptomic landscape and proposed attractor do not demonstrate fate direction, selective dependency or population immutability.", "carries_number": false, "load_bearing_for": [ "SC1", "SC5" ], "source_ns": [ 30 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C31", "text": "CloneTracer connected genotypes with differentiation routes in AML, separating healthy/pre-leukemic dormant cells from active LSC-like and downstream malignant compartments. Inferred routes and chemotherapy associations do not constitute selective in-patient stem-cell ablation or prove a universal fixed phenotype.", "carries_number": false, "load_bearing_for": [ "SC1", "SC4", "SC5" ], "source_ns": [ 31 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C32", "text": "Pre/post-mutation STRACK tracing showed driver-specific expansion of differentiation-primed stem cells and Npm1c-associated reversal toward primitive malignant states. Early engineered murine evolution is not relapse necessity across cancers, but demonstrates that cell history and mutation alter the apparent hierarchy.", "carries_number": true, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 32 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C33", "text": "Prom1 lineage tracing and depletion in two intact HCC models linked clonal expansion and dynamic dedifferentiation to tumour growth; depletion impeded growth. A lineage-state dependency in these models is not a permanently uniform marker compartment or patient-wide relapse necessity.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2", "SC4" ], "source_ns": [ 33 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C34", "text": "Integrated SCC lineage/state analyses showed chemotherapy suppressing proliferation and activating plasticity; manipulating differentiation enhanced cell-cycle-inhibitor responses. Treatment-induced state movement challenges stability but does not establish that all tumour cells are equivalently plastic or that the same switch governs every cancer.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3", "SC4" ], "source_ns": [ 34 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C35", "text": "Single-cell and lineage analyses in a defined salivary-gland SCC mouse model mapped a reproducible basal-to-stem-like-to-luminal trajectory. A developmental trajectory inferred with profiling is not ablation-defined necessity; a genetically defined model has restricted generalizability.", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 35 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C36", "text": "TNBC profiling identified FXYD3-positive ancestral/persister-like cells that persisted during neoadjuvant therapy and were sensitive to Na/K-pump inhibitors. Clinical persistence is associative and pump inhibitors affect more than CSC-specific functions; selective CSC elimination improving patient relapse-free survival was not established.", "carries_number": true, "load_bearing_for": [ "SC3", "SC4" ], "source_ns": [ 36 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C37", "text": "Anti-CD123 treatment reduced human AML xenograft engraftment and established disease burden, impaired secondary transplantation and improved mouse survival. Homing, cytokine blockade and innate effector activation are intertwined; a mouse efficacy experiment does not isolate a fixed population's necessity for human cure.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 37 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C38", "text": "Perturbing endogenous PU.1 or withdrawing differentiation treatment allowed mature AML cells in murine and human models to regain clonogenic/leukemogenic activity. This does not show unrestricted reversal in all AML genotypes, but directly challenges irreversible differentiation even in a prototypical hierarchical malignancy.", "carries_number": true, "load_bearing_for": [ "SC4", "SC5" ], "source_ns": [ 38 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C39", "text": "Ovarian PDX tumours retained heterogeneity and clinical response patterns; carboplatin/paclitaxel enriched stem-associated populations without making persisters exclusively those populations. Marker enrichment after treatment does not identify uniquely causal relapse cells or distinguish selection from induced plasticity.", "carries_number": false, "load_bearing_for": [ "SC3", "SC4" ], "source_ns": [ 39 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C40", "text": "Clonal HRAS-mutant skin models and functional pathway tests linked dynamic CSC-stromal signalling, angiogenesis and metabolic signalling to malignant transition. Interdependent niche signals support a contextual mechanism rather than a cell-intrinsic immutable hierarchy or pan-cancer necessity.", "carries_number": false, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 40 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C41", "text": "Single-cell mutation analysis and xenografts showed branching AML subclones, pre-leukemic variants and preferential but variable regenerating clones. Genetic ancestry and engraftment do not equate to fixed phenotypic stem hierarchy or independently establish post-treatment patient relapse necessity.", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 41 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C42", "text": "Functional miR-126 manipulation regulated primary AML self-renewal, differentiation and quiescence through PI3K/AKT/MTOR-associated signalling in vivo. The pathway also affects normal HSCs differently; functional perturbation in transplanted systems is not exclusive clinical LSC necessity, and an erratum is linked.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 42 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C43", "text": "Barcoded primary ALL blasts showed many approximately equipotent founders contributing through serial transplants rather than a rare dominant apex. Transplant activity is host-conditioned; this challenges rarity/exclusivity in ALL without showing that every native blast has identical fate in patients.", "carries_number": false, "load_bearing_for": [ "SC1", "SC4", "SC5" ], "source_ns": [ 43 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C44", "text": "Prostate small-cell PDXs expressed reprogramming factors, and factor transfection altered expression and stem-like colony phenotypes. Forced transcription-factor expression and colonies establish plausibility, not natural lineage conversion or fixed CSC dependence.", "carries_number": false, "load_bearing_for": [ "SC4" ], "source_ns": [ 44 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C45", "text": "Ly6d genetic perturbation in KRAS-driven pancreatic models affected a persistent gastric-like lineage and delayed tumourigenesis; human expression correlated with prognosis. A genetic lineage program and OXPHOS dependency do not prove that a discrete cell population is universally necessary or that patient relapse is prevented by targeting it.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2", "SC4" ], "source_ns": [ 45 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C46", "text": "TNBC organoids retained EMT-associated ciliated stem-like survivors after chemotherapy; genetic cilia ablation and inhibitors suppressed resistance. Organoid chemoresistance and NFkB-associated killing are not selective in-patient CSC eradication or a demonstration of permanently fixed hierarchy.", "carries_number": false, "load_bearing_for": [ "SC3", "SC4" ], "source_ns": [ 46 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C47", "text": "GATA6 loss in orthotopic CRC organoid models increased metastatic plasticity and LGR5-negative states with little primary-growth change. Genetic reprogramming shows context-specific metastatic regulation; serial transplant selection and native patient translation remain limits.", "carries_number": true, "load_bearing_for": [ "SC3", "SC4" ], "source_ns": [ 47 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C48", "text": "POLR1A-high biosynthetic CRC compartments spanned LGR5-positive and negative cells; genetic population ablation imposed irreversible growth arrest in the reported systems. Abstract-level access does not establish every model's endogenous status or exclude biosynthesis-dependent general toxicity; this functional compartment is broader than LGR5 identity.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2", "SC4" ], "source_ns": [ 48 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C49", "text": "Combined Pten/Tgfbr2 perturbation increased reprogramming, rapid prostate tumour development and early mortality with BMP/stemness-associated signalling. Multi-pathway genetic changes are not selective ablation of a fixed CSC population; survival associations do not establish human mechanistic mediation.", "carries_number": true, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 49 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C50", "text": "ABCB5-enriched melanoma cells showed serial xenograft self-renewal and antibody targeting inhibited established tumour growth. Host and assay conditions constrain rarity; antibody-mediated cytotoxicity and ABCB5 functions do not establish universal exclusive endogenous CSC maintenance.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2", "SC5" ], "source_ns": [ 50 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C51", "text": "FAK inhibition depleted a transient neural-crest-like residual melanoma state and delayed xenograft relapse, with escape favouring genetic resistance. A drug acting on a signalling network is not perfectly state-specific; delayed rather than abolished relapse illustrates alternate resistance routes.", "carries_number": false, "load_bearing_for": [ "SC3", "SC4" ], "source_ns": [ 51 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C52", "text": "Marker-sorted melanoma populations transiently overshot stem-marker equilibrium, consistent with regulated phenotypic switching after depletion. Marker dynamics and a regulatory model do not alone prove tumour-propagating function or endogenous relapse prevention failure.", "carries_number": false, "load_bearing_for": [ "SC4" ], "source_ns": [ 52 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C53", "text": "ABCB5 blockade altered an IL1/IL8/CXCR1 paracrine circuit, induced differentiation, reversed drug resistance and impaired melanoma growth in vivo. Cytokine interactions with negative cells favour a network dependency; inhibition does not establish permanently discrete CSC identity or clinical cure.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3", "SC4" ], "source_ns": [ 53 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C54", "text": "Chronic extracellular acidosis increased melanoma stem-associated and tumour-initiating properties, with a reversible phenotype linked to EMT. Artificial environmental adaptation and initiation assays establish plastic potential rather than the rate or necessity of native patient state switching.", "carries_number": false, "load_bearing_for": [ "SC4" ], "source_ns": [ 54 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C55", "text": "Reporter-tracked human intestinal tumour organoids showed lactate suppressing differentiation and inducing a proliferative stem state through acetylation/MYC-associated regulation. Organoid transitions and candidate BRD4 targeting do not demonstrate prevention of patient relapse or a unique physiological lactate mechanism.", "carries_number": false, "load_bearing_for": [ "SC4" ], "source_ns": [ 55 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C56", "text": "Intravital human CRC organoid xenograft tracing linked pre-existing LGR5/p27 dormancy to survival and post-chemotherapy expansion; COL17A1 loss and YAP interference altered sensitivity/regrowth. Human-origin transplanted systems and niche signalling do not prove a fixed population's necessity in patients; delaying regrowth is not universal eradication.", "carries_number": true, "load_bearing_for": [ "SC3", "SC4" ], "source_ns": [ 56 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C57", "text": "Anti-CD276 eliminated stem-enriched SCC cells through CD8-dependent immunity and reduced tumour growth and nodal metastases in mouse HNSCC. Immune-mediated targeting remodels several tumour states; human CD276 expression is not patient evidence that a stable CSC compartment is uniquely necessary.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 57 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C58", "text": "SHH medulloblastoma studies identified OLIG2 progenitors that changed to quiescent stem-like states; depletion/deletion impeded initiation and pathway combinations arrested growth. Therapy-resistant enrichment is not direct selective relapse prevention in children; stem-like function is developmentally and disease-context dependent.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2", "SC3", "SC4" ], "source_ns": [ 58 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C59", "text": "Direct patient melanoma cells frequently initiated serially transplantable tumours in permissive hosts; diverse markers failed to separate a large non-tumorigenic compartment and were reversible. A transplantation counterexample challenges rarity and marker exclusivity, but does not establish identical native fate for every melanoma cell.", "carries_number": false, "load_bearing_for": [ "SC1", "SC4", "SC5" ], "source_ns": [ 59 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C60", "text": "A syngeneic orthotopic intestinal organoid model identified quiescent p57-positive lineages surviving chemotherapy; their ablation suppressed post-treatment regrowth. This is a transplanted model and demonstrates suppression, not universal complete relapse prevention or an invariant CSC pool across tumours.", "carries_number": true, "load_bearing_for": [ "SC3", "SC4" ], "source_ns": [ 60 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C61", "text": "In engineered BCC models, Lgr5-positive persisters drove regrowth after vismodegib withdrawal; combined treatment removed most lesions and dual Wnt/Hedgehog inhibition prevented recurrence over the tested four-week follow-up. Human biopsies supplied phenotype/withdrawal linkage; mouse Lgr5-ablation duration was limited by normal liver toxicity, and long-term eradication was not established.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 61 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 7:Main text (unsectioned body paragraphs):paragraph5, 7:Main text (unsectioned body paragraphs):paragraph17, 7:Main text (unsectioned body paragraphs):paragraph18, 7:Main text (unsectioned body paragraphs):paragraph19, 7:Main text (unsectioned body paragraphs):paragraph21. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C62", "text": "Autochthonous lung tumour reporters, tracing and two ablation approaches showed a high-plasticity hub driving progression, burden and resistant states. Non-HPCS cells can acquire HPCS; suppression does not establish an immutable population, pan-cancer clinical necessity or durable human cure. The linked earlier version is not a second independent report.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2", "SC3", "SC4" ], "source_ns": [ 62 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 4:HPCS drives tumour growth and progression:paragraph0, 4:HPCS drives tumour growth and progression:paragraph3, 4:HPCS drives tumour growth and progression:paragraph5, 4:HPCS drives tumour growth and progression:paragraph7, 7:Discussion:paragraph0, 7:Discussion:paragraph1, 7:Discussion:paragraph2, 7:Discussion:paragraph3, 3:Non-HPCS cells can acquire the HPCS. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C63", "text": "Patient-derived CRC models showed context-dependent TROP2-positive stemness, chemotherapy-induced state redistribution and enhanced efficacy of combination TROP2-directed treatment. State-specific vulnerability and model efficacy do not demonstrate permanent cell identity or relapse-free survival benefit in patients.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3", "SC4" ], "source_ns": [ 63 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 4:TROP2 targeting and cell state remodelling:paragraph0, 5:Chemotherapy-induced TROP2 and plasticity:paragraph0, 5:Chemotherapy-induced TROP2 and plasticity:paragraph3, 5:Chemotherapy-induced TROP2 and plasticity:paragraph4. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C64", "text": "ZFP36L2 loss impaired canonical LGR5 re-entry/metastatic growth while promoting alternative heterogeneous fates; mouse regeneration tests also implicated stress-responsive dedifferentiation. Canonical stem-state dependency can be bypassed by alternative plasticity; poor-outcome associations are not a pan-cancer necessity/sufficiency test.", "carries_number": true, "load_bearing_for": [ "SC3", "SC4" ], "source_ns": [ 64 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 4:ZFP36L2 loss drives non-canonical fates, 7:Discussion. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C65", "text": "Intravital lineage tracing in unperturbed mammary tumours documented disappearance of existing stem-like contributors and formation of new ones. A dynamic lineage contribution supports plastic stemness, without measuring universal patient transition rates or showing every cancer lacks a hierarchy.", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 65 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C66", "text": "GBM stem-marker populations exhibited reversible microenvironment-instructed transitions; faster reconstitution of heterogeneity conferred an in-vivo growth advantage. Model-based and transplanted growth tests challenge discrete marker identity but do not exclude functionally important stem-like states in native gliomas.", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 66 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C67", "text": "Time-resolved colon xenograft clones linked functional stemness to edge location and fibroblast-derived osteopontin, including after chemotherapy. Quantitative model fit is not unique proof; transplanted tissue and stromal interactions limit inference about a stable intrinsic patient hierarchy.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2", "SC3", "SC4" ], "source_ns": [ 67 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "C68", "text": "Sox2 deletion reduced chemical skin tumour formation; lineage ablation and conditional deletion in established papillomas/SCCs caused regression. SOX2 regulates multiple survival and lineage functions; a strong skin-model dependency does not establish pan-cancer fixed-CSC necessity.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 68 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-06", "note": "" }, { "id": "CSC1", "text": "Endogenous skin, intestinal and glioma tracing, supported by human-origin functional assays, independently establishes functional hierarchy/stem-like contribution in defined settings. It does not establish permanent marker identity in every cancer.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 1, 2, 3, 4, 5, 6, 7, 11, 13, 16, 17, 19, 21, 22, 26, 27, 30, 31, 32, 33, 35, 41, 43, 45, 48, 50, 58, 59, 62, 65, 66, 67, 68 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-06", "note": "" }, { "id": "CSC2", "text": "Precise Sox2, Prom1 and HPCS perturbations impair growth in defined native models. Lgr5-negative CRC maintenance and context-specific niche dependence delimit the necessity claim; CSC-like function can be required without an irreplaceable fixed population.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 15, 16, 17, 18, 19, 20, 27, 28, 33, 34, 37, 40, 42, 45, 48, 49, 50, 53, 57, 58, 61, 62, 63, 67, 68 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-06", "note": "" }, { "id": "CSC3", "text": "Glioma, BCC, p57 and residual CRC tests demonstrate treatment/stage-dependent relapse dependencies. EMP1 ablation before surgery and after seeding differ; selective Lgr5 depletion can fail to prevent CRC relapse. Clinical universal relapse prevention is not demonstrated.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 11, 12, 14, 15, 18, 19, 20, 23, 24, 25, 26, 28, 29, 34, 36, 37, 39, 42, 46, 47, 51, 53, 56, 57, 58, 60, 61, 62, 63, 64, 67 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-06", "note": "" }, { "id": "CSC4", "text": "Permanent one-way membership remains a plausible local description, but mammary intravital tracing, AML differentiation reversal, CRC regrowth and HPCS re-entry directly contradict its broad stability prediction. The level records the unestablished general mechanism, not endorsement of stability.", "carries_number": false, "load_bearing_for": [ "SC4" ], "source_ns": [ 5, 6, 7, 8, 9, 10, 12, 13, 14, 15, 17, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 31, 32, 33, 34, 35, 36, 38, 39, 40, 41, 43, 44, 45, 46, 47, 48, 49, 51, 52, 53, 54, 55, 56, 58, 59, 60, 62, 63, 64, 65, 66, 67 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-06", "note": "" }, { "id": "CSC5", "text": "The preregistered cross-human-cancer fixed-population gate is not crossed. Strong causal successes in defined models do not establish the conjunction of stable hierarchy, irreplaceable membership and necessary maintenance/relapse across human haematological and solid cancers.", "carries_number": false, "load_bearing_for": [ "SC5" ], "source_ns": [ 1, 2, 3, 4, 6, 7, 11, 13, 14, 20, 27, 30, 31, 38, 43, 50, 59 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-06", "note": "" }, { "id": "CH", "text": "Functional stem-like compartments can sustain specific cancers; a fixed, universally necessary CSC hierarchy is not established.", "carries_number": false, "load_bearing_for": [ "SC5" ], "source_ns": [ 18, 68, 20, 24, 62, 59 ], "verification": "verified", "verified_against": "Bounded synthesis of examined sources; score is adjudication.", "verified_on": "2026-10-06", "note": "" } ], "citation_ledger": [ { "n": 1, "citation": "Lapidot T, Sirard C, Vormoor J et al. 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Nature medicine. 1997.", "tier": "A", "kind": "primary", "pmid": "9212098", "doi": "10.1038/nm0797-730", "url": "https://pubmed.ncbi.nlm.nih.gov/9212098/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID9212098", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C2", "CSC1", "CSC5" ] }, { "n": 3, "citation": "Al-Hajj M, Wicha MS, Benito-Hernandez A et al. Prospective identification of tumorigenic breast cancer cells. Proceedings of the National Academy of Sciences of the United States of America. 2003.", "tier": "A", "kind": "primary", "pmid": "12629218", "doi": "10.1073/pnas.0530291100", "url": "https://pubmed.ncbi.nlm.nih.gov/12629218/", "status_flags": [ "ErratumIn: PMID not supplied" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID12629218", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C3", "CSC1", "CSC5" ] }, { "n": 4, "citation": "Singh SK, Hawkins C, Clarke ID et al. Identification of human brain tumour initiating cells. Nature. 2004.", "tier": "A", "kind": "primary", "pmid": "15549107", "doi": "10.1038/nature03128", "url": "https://pubmed.ncbi.nlm.nih.gov/15549107/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID15549107", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C4", "CSC1", "CSC5" ] }, { "n": 5, "citation": "Vermeulen L, Todaro M, de Sousa Mello F et al. Single-cell cloning of colon cancer stem cells reveals a multi-lineage differentiation capacity. Proceedings of the National Academy of Sciences of the United States of America. 2008.", "tier": "A", "kind": "primary", "pmid": "18765800", "doi": "10.1073/pnas.0805706105", "url": "https://pubmed.ncbi.nlm.nih.gov/18765800/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID18765800", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C5", "CSC1", "CSC4" ] }, { "n": 6, "citation": "Quintana E, Shackleton M, Sabel MS et al. Efficient tumour formation by single human melanoma cells. Nature. 2008.", "tier": "A", "kind": "primary", "pmid": "19052619", "doi": "10.1038/nature07567", "url": "https://pubmed.ncbi.nlm.nih.gov/19052619/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID19052619", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C6", "CSC1", "CSC4", "CSC5" ] }, { "n": 7, "citation": "Held MA, Curley DP, Dankort D et al. Characterization of melanoma cells capable of propagating tumors from a single cell. Cancer research. 2010.", "tier": "A", "kind": "primary", "pmid": "20048081", "doi": "10.1158/0008-5472.CAN-09-2153", "url": "https://pubmed.ncbi.nlm.nih.gov/20048081/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID20048081", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C7", "CSC1", "CSC4", "CSC5" ] }, { "n": 8, "citation": "Mani SA, Guo W, Liao MJ et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell. 2008.", "tier": "A", "kind": "primary", "pmid": "18485877", "doi": "10.1016/j.cell.2008.03.027", "url": "https://pubmed.ncbi.nlm.nih.gov/18485877/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID18485877", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C8", "CSC4" ] }, { "n": 9, "citation": "Chaffer CL, Brueckmann I, Scheel C et al. Normal and neoplastic nonstem cells can spontaneously convert to a stem-like state. Proceedings of the National Academy of Sciences of the United States of America. 2011.", "tier": "A", "kind": "primary", "pmid": "21498687", "doi": "10.1073/pnas.1102454108", "url": "https://pubmed.ncbi.nlm.nih.gov/21498687/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID21498687", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C9", "CSC4" ] }, { "n": 10, "citation": "Gupta PB, Fillmore CM, Jiang G et al. Stochastic state transitions give rise to phenotypic equilibrium in populations of cancer cells. Cell. 2011.", "tier": "A", "kind": "primary", "pmid": "21854987", "doi": "10.1016/j.cell.2011.07.026", "url": "https://pubmed.ncbi.nlm.nih.gov/21854987/", "status_flags": [ "ErratumIn: PMID not supplied", "ErratumIn: PMID not supplied" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID21854987", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C10", "CSC4" ] }, { "n": 11, "citation": "Eppert K, Takenaka K, Lechman ER et al. Stem cell gene expression programs influence clinical outcome in human leukemia. Nature medicine. 2011.", "tier": "A", "kind": "primary", "pmid": "21873988", "doi": "10.1038/nm.2415", "url": "https://pubmed.ncbi.nlm.nih.gov/21873988/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID21873988", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C11", "CSC1", "CSC3", "CSC5" ] }, { "n": 12, "citation": "Shlush LI, Zandi S, Mitchell A et al. Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia. Nature. 2014.", "tier": "A", "kind": "primary", "pmid": "24522528", "doi": "10.1038/nature13038", "url": "https://pubmed.ncbi.nlm.nih.gov/24522528/", "status_flags": [ "ErratumIn: PMID not supplied" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID24522528", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C12", "CSC3", "CSC4" ] }, { "n": 13, "citation": "van Galen P, Hovestadt V, Wadsworth Ii MH et al. Single-Cell RNA-Seq Reveals AML Hierarchies Relevant to Disease Progression and Immunity. Cell. 2019.", "tier": "A", "kind": "primary", "pmid": "30827681", "doi": "10.1016/j.cell.2019.01.031", "url": "https://pubmed.ncbi.nlm.nih.gov/30827681/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID30827681", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C13", "CSC1", "CSC4", "CSC5" ] }, { "n": 14, "citation": "Shlush LI, Mitchell A, Heisler L et al. Tracing the origins of relapse in acute myeloid leukaemia to stem cells. Nature. 2017.", "tier": "A", "kind": "primary", "pmid": "28658204", "doi": "10.1038/nature22993", "url": "https://pubmed.ncbi.nlm.nih.gov/28658204/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID28658204", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C14", "CSC3", "CSC4", "CSC5" ] }, { "n": 15, "citation": "Kreso A, O'Brien CA, van Galen P et al. Variable clonal repopulation dynamics influence chemotherapy response in colorectal cancer. Science (New York, N.Y.). 2013.", "tier": "A", "kind": "primary", "pmid": "23239622", "doi": "10.1126/science.1227670", "url": "https://pubmed.ncbi.nlm.nih.gov/23239622/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID23239622", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C15", "CSC2", "CSC3", "CSC4" ] }, { "n": 16, "citation": "Schepers AG, Snippert HJ, Stange DE et al. Lineage tracing reveals Lgr5+ stem cell activity in mouse intestinal adenomas. Science (New York, N.Y.). 2012.", "tier": "A", "kind": "primary", "pmid": "22855427", "doi": "10.1126/science.1224676", "url": "https://pubmed.ncbi.nlm.nih.gov/22855427/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID22855427", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C16", "CSC1", "CSC2" ] }, { "n": 17, "citation": "Driessens G, Beck B, Caauwe A et al. Defining the mode of tumour growth by clonal analysis. Nature. 2012.", "tier": "A", "kind": "primary", "pmid": "22854777", "doi": "10.1038/nature11344", "url": "https://pubmed.ncbi.nlm.nih.gov/22854777/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID22854777", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C17", "CSC1", "CSC2", "CSC4" ] }, { "n": 18, "citation": "Chen J, Li Y, Yu TS et al. A restricted cell population propagates glioblastoma growth after chemotherapy. Nature. 2012.", "tier": "A", "kind": "primary", "pmid": "22854781", "doi": "10.1038/nature11287", "url": "https://pubmed.ncbi.nlm.nih.gov/22854781/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID22854781", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C18", "CSC2", "CSC3", "CH" ] }, { "n": 19, "citation": "Shimokawa M, Ohta Y, Nishikori S et al. Visualization and targeting of LGR5+ human colon cancer stem cells. Nature. 2017.", "tier": "A", "kind": "primary", "pmid": "28355176", "doi": "10.1038/nature22081", "url": "https://pubmed.ncbi.nlm.nih.gov/28355176/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID28355176", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C19", "CSC1", "CSC2", "CSC3", "CSC4" ] }, { "n": 20, "citation": "de Sousa e Melo F, Kurtova AV, Harnoss JM et al. A distinct role for Lgr5+ stem cells in primary and metastatic colon cancer. Nature. 2017.", "tier": "A", "kind": "primary", "pmid": "28358093", "doi": "10.1038/nature21713", "url": "https://pubmed.ncbi.nlm.nih.gov/28358093/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID28358093", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C20", "CSC2", "CSC3", "CSC4", "CSC5", "CH" ] }, { "n": 21, "citation": "Cortina C, Turon G, Stork D et al. A genome editing approach to study cancer stem cells in human tumors. EMBO molecular medicine. 2017.", "tier": "A", "kind": "primary", "pmid": "28468934", "doi": "10.15252/emmm.201707550", "url": "https://pubmed.ncbi.nlm.nih.gov/28468934/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID28468934", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C21", "CSC1", "CSC4" ] }, { "n": 22, "citation": "Dubash TD, Hoffmann CM, Oppel F et al. Phenotypic differentiation does not affect tumorigenicity of primary human colon cancer initiating cells. Cancer letters. 2016.", "tier": "A", "kind": "primary", "pmid": "26679053", "doi": "10.1016/j.canlet.2015.11.037", "url": "https://pubmed.ncbi.nlm.nih.gov/26679053/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID26679053", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C22", "CSC1", "CSC4" ] }, { "n": 23, "citation": "Fumagalli A, Oost KC, Kester L et al. Plasticity of Lgr5-Negative Cancer Cells Drives Metastasis in Colorectal Cancer. Cell stem cell. 2020.", "tier": "A", "kind": "primary", "pmid": "32169167", "doi": "10.1016/j.stem.2020.02.008", "url": "https://pubmed.ncbi.nlm.nih.gov/32169167/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID32169167", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C23", "CSC3", "CSC4" ] }, { "n": 24, "citation": "Cañellas-Socias A, Cortina C, Hernando-Momblona X et al. Metastatic recurrence in colorectal cancer arises from residual EMP1+ cells. Nature. 2022.", "tier": "A", "kind": "primary", "pmid": "36352230", "doi": "10.1038/s41586-022-05402-9", "url": "https://pubmed.ncbi.nlm.nih.gov/36352230/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID36352230", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 5:Relapse by residual EMP1+ cells. No complete-paper or supplement audit claimed.", "carries_claims": [ "C24", "CSC3", "CSC4", "CH" ] }, { "n": 25, "citation": "Álvarez-Varela A, Novellasdemunt L, Barriga FM et al. Mex3a marks drug-tolerant persister colorectal cancer cells that mediate relapse after chemotherapy. Nature cancer. 2022.", "tier": "A", "kind": "primary", "pmid": "35773527", "doi": "10.1038/s43018-022-00402-0", "url": "https://pubmed.ncbi.nlm.nih.gov/35773527/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID35773527", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C25", "CSC3", "CSC4" ] }, { "n": 26, "citation": "Vasquez EG, Nasreddin N, Valbuena GN et al. Dynamic and adaptive cancer stem cell population admixture in colorectal neoplasia. Cell stem cell. 2022.", "tier": "A", "kind": "primary", "pmid": "35931031", "doi": "10.1016/j.stem.2022.07.008", "url": "https://pubmed.ncbi.nlm.nih.gov/35931031/", "status_flags": [ "ErratumIn: PMID36332574" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID35931031", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C26", "CSC1", "CSC3", "CSC4" ] }, { "n": 27, "citation": "Lodestijn SC, Miedema DM, Lenos KJ et al. Marker-free lineage tracing reveals an environment-instructed clonogenic hierarchy in pancreatic cancer. Cell reports. 2021.", "tier": "A", "kind": "primary", "pmid": "34686335", "doi": "10.1016/j.celrep.2021.109852", "url": "https://pubmed.ncbi.nlm.nih.gov/34686335/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID34686335", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C27", "CSC1", "CSC2", "CSC4", "CSC5" ] }, { "n": 28, "citation": "Ball CR, Oppel F, Ehrenberg KR et al. Succession of transiently active tumor-initiating cell clones in human pancreatic cancer xenografts. 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Cancer research. 2023.", "tier": "A", "kind": "primary", "pmid": "36880956", "doi": "10.1158/0008-5472.CAN-22-2578", "url": "https://pubmed.ncbi.nlm.nih.gov/36880956/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID36880956", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C60", "CSC3", "CSC4" ] }, { "n": 61, "citation": "Sánchez-Danés A, Larsimont JC, Liagre M et al. A slow-cycling LGR5 tumour population mediates basal cell carcinoma relapse after therapy. Nature. 2018.", "tier": "A", "kind": "primary", "pmid": "30297799", "doi": "10.1038/s41586-018-0603-3", "url": "https://pubmed.ncbi.nlm.nih.gov/30297799/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID30297799", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 7:Main text (unsectioned body paragraphs):paragraph5, 7:Main text (unsectioned body paragraphs):paragraph17, 7:Main text (unsectioned body paragraphs):paragraph18, 7:Main text (unsectioned body paragraphs):paragraph19, 7:Main text (unsectioned body paragraphs):paragraph21. No complete-paper or supplement audit claimed.", "carries_claims": [ "C61", "CSC2", "CSC3" ] }, { "n": 62, "citation": "Chan JE, Pan CH, Rub J et al. Critical role for a high-plasticity cell state in lung cancer. Nature. 2026.", "tier": "A", "kind": "primary", "pmid": "41565826", "doi": "10.1038/s41586-025-09985-x", "url": "https://pubmed.ncbi.nlm.nih.gov/41565826/", "status_flags": [ "UpdateOf: PMID41278778" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID41565826", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 4:HPCS drives tumour growth and progression:paragraph0, 4:HPCS drives tumour growth and progression:paragraph3, 4:HPCS drives tumour growth and progression:paragraph5, 4:HPCS drives tumour growth and progression:paragraph7, 7:Discussion:paragraph0, 7:Discussion:paragraph1, 7:Discussion:paragraph2, 7:Discussion:paragraph3, 3:Non-HPCS cells can acquire the HPCS. No complete-paper or supplement audit claimed.", "carries_claims": [ "C62", "CSC1", "CSC2", "CSC3", "CSC4", "CH" ] }, { "n": 63, "citation": "Vaquero-Siguero N, Georgakopoulos N, Puschhof MC et al. TROP2 targeting reveals therapy-driven cell state dynamics in colorectal cancer. Nature. 2026.", "tier": "A", "kind": "primary", "pmid": "42386981", "doi": "10.1038/s41586-026-10705-2", "url": "https://pubmed.ncbi.nlm.nih.gov/42386981/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID42386981", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 4:TROP2 targeting and cell state remodelling:paragraph0, 5:Chemotherapy-induced TROP2 and plasticity:paragraph0, 5:Chemotherapy-induced TROP2 and plasticity:paragraph3, 5:Chemotherapy-induced TROP2 and plasticity:paragraph4. No complete-paper or supplement audit claimed.", "carries_claims": [ "C63", "CSC2", "CSC3", "CSC4" ] }, { "n": 64, "citation": "Jiang Q, Raghavan MS, Rodriguez AM et al. ZFP36L2 orchestrates stress-adaptive plasticity in regeneration and cancer. Nature. 2026.", "tier": "A", "kind": "primary", "pmid": "42557330", "doi": "10.1038/s41586-026-10890-0", "url": "https://pubmed.ncbi.nlm.nih.gov/42557330/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID42557330", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 4:ZFP36L2 loss drives non-canonical fates, 7:Discussion. No complete-paper or supplement audit claimed.", "carries_claims": [ "C64", "CSC3", "CSC4" ] }, { "n": 65, "citation": "Zomer A, Ellenbroek SI, Ritsma L et al. Intravital imaging of cancer stem cell plasticity in mammary tumors. Stem cells (Dayton, Ohio). 2013.", "tier": "A", "kind": "primary", "pmid": "23225641", "doi": "10.1002/stem.1296", "url": "https://pubmed.ncbi.nlm.nih.gov/23225641/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID23225641", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C65", "CSC1", "CSC4" ] }, { "n": 66, "citation": "Dirkse A, Golebiewska A, Buder T et al. Stem cell-associated heterogeneity in Glioblastoma results from intrinsic tumor plasticity shaped by the microenvironment. Nature communications. 2019.", "tier": "A", "kind": "primary", "pmid": "30992437", "doi": "10.1038/s41467-019-09853-z", "url": "https://pubmed.ncbi.nlm.nih.gov/30992437/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID30992437", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C66", "CSC1", "CSC4" ] }, { "n": 67, "citation": "Lenos KJ, Miedema DM, Lodestijn SC et al. Stem cell functionality is microenvironmentally defined during tumour expansion and therapy response in colon cancer. Nature cell biology. 2018.", "tier": "A", "kind": "primary", "pmid": "30177776", "doi": "10.1038/s41556-018-0179-z", "url": "https://pubmed.ncbi.nlm.nih.gov/30177776/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID30177776", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C67", "CSC1", "CSC2", "CSC3", "CSC4" ] }, { "n": 68, "citation": "Boumahdi S, Driessens G, Lapouge G et al. SOX2 controls tumour initiation and cancer stem-cell functions in squamous-cell carcinoma. Nature. 2014.", "tier": "A", "kind": "primary", "pmid": "24909994", "doi": "10.1038/nature13305", "url": "https://pubmed.ncbi.nlm.nih.gov/24909994/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-06", "status_checked_on": "2026-10-06", "study_id": "PMID24909994", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C68", "CSC1", "CSC2", "CH" ] } ], "independence_basis": { "required": true, "lines": [ { "label": "Native lineage contribution", "sources": [ 17, 16, 18 ], "excludes_error": "Excludes the assumption that stem-like contribution exists only because cells were transplanted; related fluorescent/Cre tracing retains marker and recombination limitations." }, { "label": "Precise native state/function perturbation", "sources": [ 68, 33, 62 ], "excludes_error": "Tests dependency beyond expression and engraftment; different skin, liver and lung backgrounds reduce one-model failure, while generalized state killing remains a shared limitation." }, { "label": "Longitudinal human ancestry and functional sampling", "sources": [ 14, 31, 41 ], "excludes_error": "Connects patient clonal history with phenotype and function, reducing wholly artificial lineage origin; sampling and transplantation selection still limit universal necessity." }, { "label": "Replacement and state reversal", "sources": [ 65, 38, 19, 59 ], "excludes_error": "Intravital tracing, endogenous transcriptional/differentiation perturbation and human-origin state assays have different principal artefacts; together challenge fixed identity rather than simply adding more marker papers." } ], "shared_failure_mode_checked": true, "note": "Independence is assessed by failure mode, not four papers equalling four causal lines. NSG xenografts, Lgr5 reporters, organoid/transplant platforms and common mutation backgrounds are explicitly shared. Distinct native tissue models, precise perturbations and patient ancestry address different errors; no complete multi-cohort provenance or blinded replication audit is claimed." }, "consensus_validation": { "completed": true, "status": "documented_historical_discovery_and_reconciliation", "provider": "Consensus", "provider_mode": "Historical browser/connector use as recorded in the source artifacts", "local_audit_date": "2026-10-09", "primary_comparison_count": null, "reported_usage": [], "grade_changed": false, "score_before": { "hsef_level": "Γ", "hsef_descriptor": "Mechanistically plausible, partial system support", "confidence": "Moderate", "confidence_rationale": "68 primary reports with 5 selected partial-body examinations; density, heterogeneous controls and incomplete access set the confidence, not correctness.", "rests_on_non_peer_reviewed_work": false, "rationale": "Γ for the exact registered broad fixed-hierarchy claim. The cancer rubric explicitly permits Ε for context-specific CSC validity; that threshold is awarded to SC2 and SC3 rather than silently replacing SC5 with a weaker functional-stemness statement. Across-context causal studies are credited as a convergent set, but their results include genuine population replacement, stage-specific dispensability and alternative lineage routes. They therefore do not cross the fixed cross-human necessity gate. Scope-matched and primary-subclaim aggregation both return Γ; weakest-link also returns Γ. Narrow existence is Ζ, and defined maintenance/relapse dependencies are Ε." }, "score_after": { "hsef_level": "Γ", "hsef_descriptor": "Mechanistically plausible, partial system support", "confidence": "Moderate", "confidence_rationale": "68 primary reports with 5 selected partial-body examinations; density, heterogeneous controls and incomplete access set the confidence, not correctness.", "rests_on_non_peer_reviewed_work": false, "rationale": "Γ for the exact registered broad fixed-hierarchy claim. The cancer rubric explicitly permits Ε for context-specific CSC validity; that threshold is awarded to SC2 and SC3 rather than silently replacing SC5 with a weaker functional-stemness statement. Across-context causal studies are credited as a convergent set, but their results include genuine population replacement, stage-specific dispensability and alternative lineage routes. They therefore do not cross the fixed cross-human necessity gate. Scope-matched and primary-subclaim aggregation both return Γ; weakest-link also returns Γ. Narrow existence is Ζ, and defined maintenance/relapse dependencies are Ε." }, "independent_blinded_audit": false, "raw_receipts": [ { "path": "deliverables\\hsef_v53_popularity_ranks_16_20_2026-10-05\\cancer-stem-cell-hierarchy\\consensus-leads-search-log.json", "sha256": "be639e19f03109bceeab6bf4fdd0001e135cb09673897adf671e90d1416366b1" }, { "path": "deliverables\\hsef_v53_popularity_ranks_16_20_2026-10-05\\cancer-stem-cell-hierarchy\\consensus\\browser-provenance.json", "sha256": "8db17f4b1236b9f3a9e51e52d995ba37855361d82aad98ec408234d74763d3bf" }, { "path": "deliverables\\hsef_v53_popularity_ranks_16_20_2026-10-05\\cancer-stem-cell-hierarchy\\consensus\\CONSENSUS_PROOF.png", "sha256": "fa1a89a0975456661cca80ccd96111fd8b578b630a756c8f7808625461fe4845" }, { "path": "deliverables\\hsef_v53_popularity_ranks_16_20_2026-10-05\\cancer-stem-cell-hierarchy\\consensus\\deep-dom.txt", "sha256": "9153ccdd401920b148596bd1aa62a4177b312997ab7b3d8d0544fa924633498c" }, { "path": "deliverables\\hsef_v53_popularity_ranks_16_20_2026-10-05\\cancer-stem-cell-hierarchy\\consensus\\deep-response.txt", "sha256": "59897ea6dd98641bb703a8965fbfc8cad1d640daa8e62debe66e3e59a78ac18a" } ], "limitations": "This verifies documented historical use and links the record to the final edition. It adds no primary-source, full-text, independence or verification credit. Original access remains limited to the source-specific record." } }