{ "$schema_version": "5.3", "review_mode": "fresh", "claim_restatement": { "index_wording": "Tumor Microenvironment-driven Progression", "entry_form": "phenomenon", "gradeable_restatement": "Tumor-microenvironment factors are primary drivers of malignant maintenance and progression, dominating cell-autonomous genetic and epigenetic drivers.", "restatement_required": true, "split_into": [], "parent_claim": null, "scope_qualifiers": [ { "qualifier": "Tumor genotype, anatomic site, stage, immune competence, CAF/matrix subtype and treatment timing", "determinable_before_outcome": true, "determined_from": "Enrollment and experimental design, before results; no responder-defined scope.", "action": "retained" } ] }, "hypothesis": { "name": "Tumor Microenvironment-driven Progression", "central_claim": "Tumor-microenvironment factors are primary drivers of malignant maintenance and progression, dominating cell-autonomous genetic and epigenetic drivers.", "proposed_mechanism": "Tumor-microenvironment factors are primary drivers of malignant maintenance and progression, dominating cell-autonomous genetic and epigenetic drivers.", "claimed_scope": "Causal influence of prespecified immune/stromal/matrix compartments and their primacy over intrinsic programs in malignant maintenance/progression, with tumor genotype and stage fixed in advance.", "claimed_level": [ "maintenance", "progression", "relapse" ], "is_conjunctive": true, "conjunctive_note": "Use the index primacy distinction, retaining maintenance/progression scope. Influence is tested separately and cannot establish dominance. Immune and fibroblast/matrix compartments can differ in sign by stage; primacy needs explicit paired cell-autonomous comparison." }, "rubric_routing": { "primary_rubric": "02-cancer-biology.md", "secondary_rubrics": [ "05-immunology-inflammation.md" ], "index_notes_applied": [ "Use the index primacy distinction, retaining maintenance/progression scope. Influence is tested separately and cannot establish dominance. Immune and fibroblast/matrix compartments can differ in sign by stage; primacy needs explicit paired cell-autonomous comparison." ], "rubric_fit_note": "Exact archived v5.3 framework. Any stale index empirical framing is rechecked against primary results." }, "subclaim_matrix": { "subclaims": [ { "id": "SC1", "statement": "The tumor microenvironment causally influences tumor behavior.", "subclaim_type": "mechanism", "scope": "prespecified immune, stromal and matrix compartments", "claimed_scope": "prespecified immune, stromal and matrix compartments", "governing_rubric": "02-cancer-biology.md", "key_evidence_anchor": "Endogenous compartment perturbation with tumor/survival outcomes", "hsef_level": "Η", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Η: endogenous compartment-specific loss, immune restoration, relapse/resistance tests and independent clinical survival interventions establish causal TME influence within explicitly defined compartments/settings. They reject the claim that all TME change is reactive; they do not make every stromal factor rate-limiting." }, { "id": "SC2", "statement": "Microenvironment factors dominate cell-autonomous drivers in maintenance and progression.", "subclaim_type": "primacy", "scope": "tumor genotype and stage defined before outcome", "claimed_scope": "tumor genotype and stage defined before outcome", "governing_rubric": "02-cancer-biology.md", "key_evidence_anchor": "Paired microenvironment/driver subtraction, rescue and longitudinal clonal tracking", "hsef_level": "Γ", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Γ: scoped host-dependent resistance and tissue-humanization models support primacy as a mechanistic possibility. Paired evidence also shows continued intrinsic dependencies and joint immune/oncogene requirements. The registered general dominance claim lacks convergent endogenous factorial comparisons; influence cannot substitute for primacy." } ], "aggregation_rule": "primary-subclaim", "aggregation_preregistered": true, "aggregation_rationale": "Use the index primacy distinction, retaining maintenance/progression scope. Influence is tested separately and cannot establish dominance. Immune and fibroblast/matrix compartments can differ in sign by stage; primacy needs explicit paired cell-autonomous comparison.", "primary_subclaim_id": "SC2", "aggregation_derivation": "Preregistered primary-subclaim SC2 returns Γ. Weakest-link and scope-matched sensitivities also return Γ; SC1 influence reaches Η independently. A narrow macrophage-dependent acquired-resistance state can cross Ε contribution/conditional dominance, but it does not replace the registered broad maintenance/progression claim.", "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": "Dual-function context-dependent stroma", "core_claim": "Immune, stromal and matrix compartments interact with intrinsic programs, with effects changing sign by cell subset, stage and treatment.", "explains_what_nominal_does_not": "Immune, stromal and matrix compartments interact with intrinsic programs, with effects changing sign by cell subset, stage and treatment.", "strongest_supporting_evidence": [ "Opposite FAP/alphaSMA effects, collagen/receptor rescue and genotype/host withdrawal: PMID35348629,33667385,21035406,27199435." ], "strongest_contradictory_evidence": [ "Not a fully parameterized predictive theory; related CAF platforms reduce independence and signs require prespecified context." ], "hsef_level_for_this_model": "Ζ", "rationale": "Opposite FAP/alphaSMA effects, collagen/receptor rescue and genotype/host withdrawal: PMID35348629,33667385,21035406,27199435. Not a fully parameterized predictive theory; related CAF platforms reduce independence and signs require prespecified context." }, { "rank_in_tournament": 2, "model_id": "M2", "is_nominal": false, "name": "Immune-compartment causality", "core_claim": "Defined immune effectors causally control malignant escape and durable treatment outcomes.", "explains_what_nominal_does_not": "Defined immune effectors causally control malignant escape and durable treatment outcomes.", "strongest_supporting_evidence": [ "Endogenous equilibrium/immunoediting, host restoration and independent checkpoint trials: PMID18026089,22318521,21035406,26028407,27718847,39282897." ], "strongest_contradictory_evidence": [ "Some cancers/regimens escape or do not benefit; immune control does not establish all-TME or all-cancer primacy." ], "hsef_level_for_this_model": "Η", "rationale": "Endogenous equilibrium/immunoediting, host restoration and independent checkpoint trials: PMID18026089,22318521,21035406,26028407,27718847,39282897. Some cancers/regimens escape or do not benefit; immune control does not establish all-TME or all-cancer primacy." }, { "rank_in_tournament": 3, "model_id": "M3", "is_nominal": false, "name": "Cell-autonomous drivers with permissive niche", "core_claim": "Intrinsic drivers remain required while host conditions supply support or determine eradication/escape.", "explains_what_nominal_does_not": "Intrinsic drivers remain required while host conditions supply support or determine eradication/escape.", "strongest_supporting_evidence": [ "KRAS/MYC/p53 withdrawal/restoration and intrinsic immune escape: PMID22232209,17251932,21035406,27433843." ], "strongest_contradictory_evidence": [ "Permissive understates active immune selection and niche-determined resistance; intrinsic lesions can be bypassed by alternative immune routes, PMID32467343." ], "hsef_level_for_this_model": "Ε", "rationale": "KRAS/MYC/p53 withdrawal/restoration and intrinsic immune escape: PMID22232209,17251932,21035406,27433843. Permissive understates active immune selection and niche-determined resistance; intrinsic lesions can be bypassed by alternative immune routes, PMID32467343." }, { "rank_in_tournament": 4, "model_id": "M5", "is_nominal": false, "name": "Stroma as host containment", "core_claim": "Selected matrix/myofibroblast and immune programs restrain growth or maintain dormancy.", "explains_what_nominal_does_not": "Selected matrix/myofibroblast and immune programs restrain growth or maintain dormancy.", "strongest_supporting_evidence": [ "AlphaSMA/collagen depletion and vascular dormancy: PMID24856586,33667385,23728425." ], "strongest_contradictory_evidence": [ "Other CAF compartments promote growth and Hh effects differ by protocol; host containment is not all-stroma universal suppression." ], "hsef_level_for_this_model": "Ε", "rationale": "AlphaSMA/collagen depletion and vascular dormancy: PMID24856586,33667385,23728425. Other CAF compartments promote growth and Hh effects differ by protocol; host containment is not all-stroma universal suppression." }, { "rank_in_tournament": 5, "model_id": "M1", "is_nominal": true, "name": "Microenvironment primacy", "core_claim": "Host factors generally dominate intrinsic malignant maintenance/progression.", "explains_what_nominal_does_not": "Host factors generally dominate intrinsic malignant maintenance/progression.", "strongest_supporting_evidence": [ "Breast humanization and reversible host-dependent glioma resistance: PMID15051869,27199435." ], "strongest_contradictory_evidence": [ "Occult donor clones, endogenous KRAS dependence and combined intrinsic/immune requirements block broad dominance." ], "hsef_level_for_this_model": "Γ", "rationale": "Breast humanization and reversible host-dependent glioma resistance: PMID15051869,27199435. Occult donor clones, endogenous KRAS dependence and combined intrinsic/immune requirements block broad dominance." } ], "tournament_summary": "Descriptive comparison; does not modify the nominal score. Prospectively compare driver suppression and defined host-compartment perturbation factorially in the same genotype/stage, with equal engagement, restoration of each layer and clone-resolved relapse. This separates joint dependence from true causal priority.", "study_separating_rank1_from_rank2": "Prospectively compare driver suppression and defined host-compartment perturbation factorially in the same genotype/stage, with equal engagement, restoration of each layer and clone-resolved relapse. This separates joint dependence from true causal priority.", "nominal_wins_only_by_funding_artifact": false, "level_unchanged_by_tournament": true }, "evidence_inventory": [ { "n": 1, "pmid": "10519415", "title": "Carcinoma-associated fibroblasts direct tumor progression of initiated human prostatic epithelium.", "citation": "Olumi AF, Grossfeld GD, Hayward SW et al. Carcinoma-associated fibroblasts direct tumor progression of initiated human prostatic epithelium. Cancer research. 1999.", "doi": "", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/10519415/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/10519415/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID10519415", "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": "Moderate", "system": "human epithelial/fibroblast coimplantation", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Carcinoma-associated versus normal fibroblasts promote tumor growth from initiated, nontumorigenic prostate epithelium.", "what_it_does_not_show": "Initiated epithelium and xenograft context; not conversion of genetically verified uninitiated cells or general extrinsic dominance.", "confounders_present": [ "Initiated epithelium and xenograft context; not conversion of genetically verified uninitiated cells or general extrinsic dominance." ], "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": 2, "pmid": "15051869", "title": "Reconstruction of functionally normal and malignant human breast tissues in mice.", "citation": "Kuperwasser C, Chavarria T, Wu M et al. Reconstruction of functionally normal and malignant human breast tissues in mice. Proceedings of the National Academy of Sciences of the United States of America. 2004.", "doi": "10.1073/pnas.0401064101", "pmcid": "PMC387357", "url": "https://pubmed.ncbi.nlm.nih.gov/15051869/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/15051869/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID15051869", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:Publisher HTML paragraphs:paragraph16, 0:Publisher HTML paragraphs:paragraph17, 0:Publisher HTML paragraphs:paragraph39, 0:Publisher HTML paragraphs:paragraph40, 0:Publisher HTML paragraphs:paragraph42, 0:Publisher HTML paragraphs:paragraph43, 0:Publisher HTML paragraphs:paragraph44, 0:Publisher HTML paragraphs:paragraph45, 0:Publisher HTML paragraphs:paragraph46, 0:Publisher HTML paragraphs:paragraph47, 0:Publisher HTML paragraphs:paragraph48, 0:Publisher HTML paragraphs:paragraph53. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "humanized mammary xenograft", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Growth-factor-modified stroma produces malignant outgrowth in 16/18 grafts from one donor; adding normal fibroblasts prevents abnormal outgrowth.", "what_it_does_not_show": "Nine of ten donors remain nonmalignant and a different region of the responding breast fails to reproduce malignancy; DNA identity is not exclusion of occult premalignant clones.", "confounders_present": [ "Nine of ten donors remain nonmalignant and a different region of the responding breast fails to reproduce malignancy; DNA identity is not exclusion of occult premalignant clones." ], "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": 3, "pmid": "15882617", "title": "Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion.", "citation": "Orimo A, Gupta PB, Sgroi DC et al. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell. 2005.", "doi": "10.1016/j.cell.2005.02.034", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/15882617/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/15882617/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID15882617", "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" ], "favors_models": [], "evidence_class": "Moderate", "system": "matched human CAF coimplantation", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "CAFs from human breast cancers promote growth through SDF1/CXCL12-associated angiogenic recruitment and epithelial CXCR4 signaling.", "what_it_does_not_show": "Coimplantation with established cancer cells and coupled angiogenesis/proliferation do not establish endogenous universal dominance.", "confounders_present": [ "Coimplantation with established cancer cells and coupled angiogenesis/proliferation do not establish endogenous universal dominance." ], "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": 4, "pmid": "19931152", "title": "Matrix crosslinking forces tumor progression by enhancing integrin signaling.", "citation": "Levental KR, Yu H, Kass L et al. Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell. 2009.", "doi": "10.1016/j.cell.2009.10.027", "pmcid": "PMC2788004", "url": "https://pubmed.ncbi.nlm.nih.gov/19931152/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/19931152/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID19931152", "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": "autochthonous mammary matrix intervention", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "LOX-linked matrix crosslinking promotes integrin signaling and invasion; blocking crosslinking reduces fibrosis, tumor incidence and progression.", "what_it_does_not_show": "Oncogene-initiated context; changing mechanics/signaling together is not proof that the matrix overrides all tumor genotypes.", "confounders_present": [ "Oncogene-initiated context; changing mechanics/signaling together is not proof that the matrix overrides all tumor genotypes." ], "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": 5, "pmid": "21729786", "title": "Biomechanical remodeling of the microenvironment by stromal caveolin-1 favors tumor invasion and metastasis.", "citation": "Goetz JG, Minguet S, Navarro-Lérida I et al. Biomechanical remodeling of the microenvironment by stromal caveolin-1 favors tumor invasion and metastasis. Cell. 2011.", "doi": "10.1016/j.cell.2011.05.040", "pmcid": "PMC3244213", "url": "https://pubmed.ncbi.nlm.nih.gov/21729786/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/21729786/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID21729786", "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" ], "favors_models": [], "evidence_class": "Moderate", "system": "mouse fibroblast/host and human association", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Fibroblast caveolin1 influences matrix remodeling, stiffness and invasion with Rho/p190 signaling contrasts.", "what_it_does_not_show": "Global host knockout/development and human prognosis association constrain compartment specificity and primacy.", "confounders_present": [ "Global host knockout/development and human prognosis association constrain compartment specificity and primacy." ], "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": "26676755", "title": "Injury-Driven Stiffening of the Dermis Expedites Skin Carcinoma Progression.", "citation": "Mittapalli VR, Madl J, Löffek S et al. Injury-Driven Stiffening of the Dermis Expedites Skin Carcinoma Progression. Cancer research. 2016.", "doi": "10.1158/0008-5472.CAN-15-1348", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/26676755/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26676755/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID26676755", "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": "collagenVII-hypomorphic injury/carcinogen mouse", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "A wound/fibrotic environment promotes squamous carcinogenesis with TGFbeta/LOX/integrin pathway contrasts.", "what_it_does_not_show": "Chemical initiation and chronic injury accompany matrix changes; mutation-independent wording does not prove identical normal epithelial genomes/clones.", "confounders_present": [ "Chemical initiation and chronic injury accompany matrix changes; mutation-independent wording does not prove identical normal epithelial genomes/clones." ], "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": 7, "pmid": "31406163", "title": "CAF hierarchy driven by pancreatic cancer cell p53-status creates a pro-metastatic and chemoresistant environment via perlecan.", "citation": "Vennin C, Mélénec P, Rouet R et al. CAF hierarchy driven by pancreatic cancer cell p53-status creates a pro-metastatic and chemoresistant environment via perlecan. Nature communications. 2019.", "doi": "10.1038/s41467-019-10968-6", "pmcid": "PMC6691013", "url": "https://pubmed.ncbi.nlm.nih.gov/31406163/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31406163/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID31406163", "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": "tumor p53/CAF perlecan perturbation", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Tumor gain-of-function p53 educates fibroblasts into a perlecan-rich niche supporting invasion and therapy resistance.", "what_it_does_not_show": "Tumor genotype organizes the host phenotype; dominance of one CAF state over another is not dominance of host over tumor drivers.", "confounders_present": [ "Tumor genotype organizes the host phenotype; dominance of one CAF state over another is not dominance of host over tumor drivers." ], "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": "28232471", "title": "Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer.", "citation": "Öhlund D, Handly-Santana A, Biffi G et al. Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer. The Journal of experimental medicine. 2017.", "doi": "10.1084/jem.20162024", "pmcid": "PMC5339682", "url": "https://pubmed.ncbi.nlm.nih.gov/28232471/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/28232471/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID28232471", "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" ], "favors_models": [], "evidence_class": "Moderate", "system": "human/mouse pancreatic CAF mapping and coculture", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Spatially distinct inflammatory and myofibroblastic CAF states emerge in pancreatic models and tissue.", "what_it_does_not_show": "Phenotype/state mapping alone is not a survival perturbation or causal hierarchy.", "confounders_present": [ "Phenotype/state mapping alone is not a survival perturbation or causal 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": 9, "pmid": "30366930", "title": "IL1-Induced JAK/STAT Signaling Is Antagonized by TGFβ to Shape CAF Heterogeneity in Pancreatic Ductal Adenocarcinoma.", "citation": "Biffi G, Oni TE, Spielman B et al. IL1-Induced JAK/STAT Signaling Is Antagonized by TGFβ to Shape CAF Heterogeneity in Pancreatic Ductal Adenocarcinoma. Cancer discovery. 2019.", "doi": "10.1158/2159-8290.CD-18-0710", "pmcid": "PMC6368881", "url": "https://pubmed.ncbi.nlm.nih.gov/30366930/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30366930/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID30366930", "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" ], "favors_models": [], "evidence_class": "Moderate", "system": "CAF pathway perturbation in pancreatic models", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "IL1/LIF/JAKSTAT promotes inflammatory CAFs while TGFbeta suppresses IL1R1 and favors myofibroblastic states.", "what_it_does_not_show": "Tumor ligand output and CAF plasticity are coupled; state selection is not broad malignant maintenance primacy.", "confounders_present": [ "Tumor ligand output and CAF plasticity are coupled; state selection is not broad malignant maintenance primacy." ], "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": "35348629", "title": "Identification of Functional Heterogeneity of Carcinoma-Associated Fibroblasts with Distinct IL6-Mediated Therapy Resistance in Pancreatic Cancer.", "citation": "McAndrews KM, Chen Y, Darpolor JK et al. Identification of Functional Heterogeneity of Carcinoma-Associated Fibroblasts with Distinct IL6-Mediated Therapy Resistance in Pancreatic Cancer. Cancer discovery. 2022.", "doi": "10.1158/2159-8290.CD-20-1484", "pmcid": "PMC9399904", "url": "https://pubmed.ncbi.nlm.nih.gov/35348629/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35348629/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID35348629", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:Publisher HTML paragraphs:paragraph24, 0:Publisher HTML paragraphs:paragraph25, 0:Publisher HTML paragraphs:paragraph28, 0:Publisher HTML paragraphs:paragraph35, 0:Publisher HTML paragraphs:paragraph36, 0:Publisher HTML paragraphs:paragraph39, 0:Publisher HTML paragraphs:paragraph40, 0:Publisher HTML paragraphs:paragraph41, 0:Publisher HTML paragraphs:paragraph42, 0:Publisher HTML paragraphs:paragraph43, 0:Publisher HTML paragraphs:paragraph44, 0:Publisher HTML paragraphs:paragraph56, 0:Publisher HTML paragraphs:paragraph67, 0:Publisher HTML paragraphs:paragraph80, 0:Publisher HTML paragraphs:paragraph38, 0:Publisher HTML paragraphs:paragraph45, 0:Publisher HTML paragraphs:paragraph46, 0:Publisher HTML paragraphs:paragraph50, 0:Publisher HTML paragraphs:paragraph57, 0:Publisher HTML paragraphs:paragraph47, 0:Publisher HTML paragraphs:paragraph48, 0:Publisher HTML paragraphs:paragraph49. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "autochthonous compartment depletion/IL6 deletion", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "FAP-positive CAF depletion improves survival whereas alphaSMA-positive depletion worsens it; alphaSMA-specific IL6 loss improves gemcitabine response.", "what_it_does_not_show": "Baseline IL6 deletion leaves progression/survival similar; global IL6 knockout, not solely conditional alphaSMA deletion, supports the tested triple therapy. No allocation randomization, histology blinded; reused alphaSMA data are not independent replication.", "confounders_present": [ "Baseline IL6 deletion leaves progression/survival similar; global IL6 knockout, not solely conditional alphaSMA deletion, supports the tested triple therapy. No allocation randomization, histology blinded; reused alphaSMA data are not independent replication." ], "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": [ "AlphaSMA expression data GSE52812 reused from PMID24856586; new FAP experiments distinct." ] }, { "n": 11, "pmid": "24856585", "title": "Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma.", "citation": "Rhim AD, Oberstein PE, Thomas DH et al. Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. Cancer cell. 2014.", "doi": "10.1016/j.ccr.2014.04.021", "pmcid": "PMC4096698", "url": "https://pubmed.ncbi.nlm.nih.gov/24856585/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/24856585/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID24856585", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:RESULTS:paragraph0, 1:RESULTS:paragraph1, 1:RESULTS:paragraph2, 1:RESULTS:paragraph4, 1:RESULTS:paragraph6, 1:RESULTS:paragraph7, 1:RESULTS:paragraph11, 1:RESULTS:paragraph13. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "autochthonous epithelial SHH deletion and chronic Smo blockade", "decisive_perturbation": true, "endogenous": true, "direction": "contradicts", "what_it_shows": "SHH loss reduces stroma but median survival falls from 6.17 to 3.61 months and gross metastasis rises from 15.3 to 43.4 percent; VEGFR2 blockade selectively rescues the stroma-low setting.", "what_it_does_not_show": "SHH deletion is epithelial, not stromal-only; chronic versus acute blockade can have different signs. A suppressive stromal contribution does not prove opposite universal genetic dominance.", "confounders_present": [ "SHH deletion is epithelial, not stromal-only; chronic versus acute blockade can have different signs. A suppressive stromal contribution does not prove opposite universal genetic dominance." ], "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": "24856586", "title": "Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival.", "citation": "Özdemir BC, Pentcheva-Hoang T, Carstens JL et al. Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer cell. 2014.", "doi": "10.1016/j.ccr.2014.04.005", "pmcid": "PMC4180632", "url": "https://pubmed.ncbi.nlm.nih.gov/24856586/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/24856586/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID not supplied" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID24856586", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph0, 1:Results:paragraph1, 1:Results:paragraph5, 1:Results:paragraph6, 1:Results:paragraph8. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "autochthonous alphaSMA depletion and immune bypass", "decisive_perturbation": true, "endogenous": true, "direction": "contradicts", "what_it_shows": "Approximately 80 percent myofibroblast depletion accelerates aggressive disease and shortens survival despite lower tumor weight; antiCTLA4 increases median survival to 65 versus control 47 days.", "what_it_does_not_show": "Pulmonary emboli contribute to mortality; sphere/marker enrichment is not CSC proof. Rescue bypasses rather than restores depleted fibroblasts; linked erratum contents unexamined.", "confounders_present": [ "Pulmonary emboli contribute to mortality; sphere/marker enrichment is not CSC proof. Rescue bypasses rather than restores depleted fibroblasts; linked erratum contents unexamined." ], "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": [ "Related alphaSMA/PDAC experimental lineage to PMID33667385,35348629." ] }, { "n": 13, "pmid": "25024225", "title": "Stromal response to Hedgehog signaling restrains pancreatic cancer progression.", "citation": "Lee JJ, Perera RM, Wang H et al. Stromal response to Hedgehog signaling restrains pancreatic cancer progression. Proceedings of the National Academy of Sciences of the United States of America. 2014.", "doi": "10.1073/pnas.1411679111", "pmcid": "PMC4121834", "url": "https://pubmed.ncbi.nlm.nih.gov/25024225/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25024225/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID25024225", "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": "three pancreatic GEMMs and Hh pharmacology", "decisive_perturbation": true, "endogenous": true, "direction": "contradicts", "what_it_shows": "Hedgehog inhibition accelerates pancreatic disease whereas pathway activation expands stroma and reduces epithelial proliferation.", "what_it_does_not_show": "Stage, genotype and protocol restrict sign; all CAFs and all Hh contexts cannot be called tumor suppressive.", "confounders_present": [ "Stage, genotype and protocol restrict sign; all CAFs and all Hh contexts cannot be called tumor suppressive." ], "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": "33667385", "title": "Type I collagen deletion in αSMA+ myofibroblasts augments immune suppression and accelerates progression of pancreatic cancer.", "citation": "Chen Y, Kim J, Yang S et al. Type I collagen deletion in αSMA+ myofibroblasts augments immune suppression and accelerates progression of pancreatic cancer. Cancer cell. 2021.", "doi": "10.1016/j.ccell.2021.02.007", "pmcid": "PMC8423173", "url": "https://pubmed.ncbi.nlm.nih.gov/33667385/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33667385/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID33667385", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:RESULTS:paragraph0, 1:RESULTS:paragraph1, 1:RESULTS:paragraph6, 1:RESULTS:paragraph7, 1:RESULTS:paragraph8, 1:RESULTS:paragraph11, 1:RESULTS:paragraph20. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "dual-recombinase autochthonous stromal collagen deletion", "decisive_perturbation": true, "endogenous": true, "direction": "contradicts", "what_it_shows": "AlphaSMA-specific Col1 deletion reduces fibrillar collagen/stiffness and accelerates PDAC; CXCR2/CCR2 blockade restores survival toward control.", "what_it_does_not_show": "Fsp1-directed deletion does not similarly reduce total collagen or survival; immune bypass does not restore matrix. Shows compartment-specific restraint rather than generic collagen protection.", "confounders_present": [ "Fsp1-directed deletion does not similarly reduce total collagen or survival; immune bypass does not restore matrix. Shows compartment-specific restraint rather than generic collagen protection." ], "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": "33495315", "title": "Inhibition of Hedgehog Signaling Alters Fibroblast Composition in Pancreatic Cancer.", "citation": "Steele NG, Biffi G, Kemp SB et al. Inhibition of Hedgehog Signaling Alters Fibroblast Composition in Pancreatic Cancer. Clinical cancer research : an official journal of the American Association for Cancer Research. 2021.", "doi": "10.1158/1078-0432.CCR-20-3715", "pmcid": "PMC8026631", "url": "https://pubmed.ncbi.nlm.nih.gov/33495315/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33495315/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID33495315", "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": "pancreatic Hh/CAF intervention", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "SHH overexpression promotes growth and Smo inhibition impairs it while shifting myCAF/iCAF and immune composition.", "what_it_does_not_show": "Contrasts earlier restraining-Hh settings; different stage/protocols prevent one universal directional story.", "confounders_present": [ "Contrasts earlier restraining-Hh settings; different stage/protocols prevent one universal directional story." ], "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": "24277834", "title": "Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer.", "citation": "Feig C, Jones JO, Kraman M et al. Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. Proceedings of the National Academy of Sciences of the United States of America. 2013.", "doi": "10.1073/pnas.1320318110", "pmcid": "PMC3864274", "url": "https://pubmed.ncbi.nlm.nih.gov/24277834/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/24277834/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID24277834", "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": "autochthonous pancreatic CAF/CXCL12/checkpoint perturbation", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "FAP-cell and CXCL12 contrasts identify immune exclusion; AMD3100 plus antiPDL1 rapidly removes tumor cells in a defined pancreatic model.", "what_it_does_not_show": "Combined immune/niche dependence in a driver-bearing tumor does not establish host primacy over all intrinsic programs.", "confounders_present": [ "Combined immune/niche dependence in a driver-bearing tumor does not establish host primacy over all intrinsic programs." ], "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": "29443960", "title": "TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells.", "citation": "Mariathasan S, Turley SJ, Nickles D et al. TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature. 2018.", "doi": "10.1038/nature25501", "pmcid": "PMC6028240", "url": "https://pubmed.ncbi.nlm.nih.gov/29443960/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29443960/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID29443960", "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": "human urothelial association plus mouse intervention", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "TGFbeta-rich stroma associates with immune exclusion; combined TGFbeta/PDL1 blockade restores penetration and regression in mouse tumors.", "what_it_does_not_show": "Human biomarker associations are not randomized compartment comparisons; combination efficacy cannot isolate a universal dominant layer.", "confounders_present": [ "Human biomarker associations are not randomized compartment comparisons; combination efficacy cannot isolate a universal dominant layer." ], "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": "29443964", "title": "TGFβ drives immune evasion in genetically reconstituted colon cancer metastasis.", "citation": "Tauriello DVF, Palomo-Ponce S, Stork D et al. TGFβ drives immune evasion in genetically reconstituted colon cancer metastasis. Nature. 2018.", "doi": "10.1038/nature25492", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/29443964/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29443964/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID29443964", "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": "genetically reconstituted metastatic colorectal model", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "TGFbeta blockade prevents metastasis and enables checkpoint control of established lesions in low-mutational-burden driver-mutant CRC.", "what_it_does_not_show": "Specific immune-evasion dependence in a defined tumor genotype; does not erase the required epithelial driver program.", "confounders_present": [ "Specific immune-evasion dependence in a defined tumor genotype; does not erase the required epithelial driver program." ], "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": "24056773", "title": "CSF-1R inhibition alters macrophage polarization and blocks glioma progression.", "citation": "Pyonteck SM, Akkari L, Schuhmacher AJ et al. CSF-1R inhibition alters macrophage polarization and blocks glioma progression. Nature medicine. 2013.", "doi": "10.1038/nm.3337", "pmcid": "PMC3840724", "url": "https://pubmed.ncbi.nlm.nih.gov/24056773/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/24056773/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID24056773", "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" ], "favors_models": [], "evidence_class": "Strong", "system": "PDGF glioma macrophage intervention", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "CSF1R inhibition regresses glioma and prolongs survival through macrophage-state alteration.", "what_it_does_not_show": "TAMs are protected from depletion by glioma signals; functional repolarization, not simply fewer macrophages, explains the tested response.", "confounders_present": [ "TAMs are protected from depletion by glioma signals; functional repolarization, not simply fewer macrophages, explains the tested response." ], "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": 20, "pmid": "27199435", "title": "The tumor microenvironment underlies acquired resistance to CSF-1R inhibition in gliomas.", "citation": "Quail DF, Bowman RL, Akkari L et al. The tumor microenvironment underlies acquired resistance to CSF-1R inhibition in gliomas. Science (New York, N.Y.). 2016.", "doi": "10.1126/science.aad3018", "pmcid": "PMC5450629", "url": "https://pubmed.ncbi.nlm.nih.gov/27199435/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/27199435/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID27199435", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:A subset of GBMs develop resistance to CSF-1R inhibition in long-term preclinical trials, 2:Resistance to CSF-1R inhibition is mediated by the microenvironment, 6:Combination of CSF-1R and IGF-1R inhibition improves outcome. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "autochthonous glioma acquired resistance and retransplantation", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Continued CSF1R blockade produces rebound in 56 percent; rebound cells regain sensitivity in naive hosts, and IGF1R plus CSF1R inhibition extends recurrent-tumor median survival from 13 to 63 days.", "what_it_does_not_show": "Passaging/transplantation can reset state; tumor-specific IGF1R knockdown also restores response. Strong scoped environmental resistance control does not establish general malignant primacy.", "confounders_present": [ "Passaging/transplantation can reset state; tumor-specific IGF1R knockdown also restores response. Strong scoped environmental resistance control does not establish general malignant primacy." ], "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": 21, "pmid": "27840052", "title": "Macrophage Ontogeny Underlies Differences in Tumor-Specific Education in Brain Malignancies.", "citation": "Bowman RL, Klemm F, Akkari L et al. Macrophage Ontogeny Underlies Differences in Tumor-Specific Education in Brain Malignancies. Cell reports. 2016.", "doi": "10.1016/j.celrep.2016.10.052", "pmcid": "PMC5450644", "url": "https://pubmed.ncbi.nlm.nih.gov/27840052/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/27840052/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID27840052", "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" ], "favors_models": [], "evidence_class": "Strong", "system": "endogenous macrophage lineage tracing", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Nonirradiative lineage tracing distinguishes brain-resident and recruited macrophage origins with different programs in glioma.", "what_it_does_not_show": "Ontogeny and epigenetic association do not alone establish growth dependency or primacy.", "confounders_present": [ "Ontogeny and epigenetic association do not alone establish growth dependency or primacy." ], "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": "21822305", "title": "Deficiency of the macrophage growth factor CSF-1 disrupts pancreatic neuroendocrine tumor development.", "citation": "Pyonteck SM, Gadea BB, Wang HW et al. Deficiency of the macrophage growth factor CSF-1 disrupts pancreatic neuroendocrine tumor development. Oncogene. 2012.", "doi": "10.1038/onc.2011.337", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/21822305/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/21822305/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID21822305", "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" ], "favors_models": [], "evidence_class": "Strong", "system": "autochthonous PNET CSF1 genetic deficiency", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "CSF1 deficiency reduces macrophages, angiogenic switching and total pancreatic neuroendocrine tumor burden.", "what_it_does_not_show": "Established tumors retain growth with compensating neutrophils; developmental effects and redundant myeloid routes limit universal necessity.", "confounders_present": [ "Established tumors retain growth with compensating neutrophils; developmental effects and redundant myeloid routes limit universal 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": 23, "pmid": "17114237", "title": "Macrophages regulate the angiogenic switch in a mouse model of breast cancer.", "citation": "Lin EY, Li JF, Gnatovskiy L et al. Macrophages regulate the angiogenic switch in a mouse model of breast cancer. Cancer research. 2006.", "doi": "10.1158/0008-5472.CAN-06-1278", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/17114237/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/17114237/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID17114237", "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" ], "favors_models": [], "evidence_class": "Strong", "system": "autochthonous mammary macrophage loss and restoration", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Macrophage recruitment promotes an angiogenic switch; blocked infiltration delays progression and local restoration restores vascular effects.", "what_it_does_not_show": "A defined angiogenic stage and transgenic platform, not all epithelial initiation or maintenance.", "confounders_present": [ "A defined angiogenic stage and transgenic platform, not all epithelial initiation or 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": 24, "pmid": "37798557", "title": "Depletion of slow-cycling PDGFRα+ADAM12+ mesenchymal cells promotes antitumor immunity by restricting macrophage efferocytosis.", "citation": "Di Carlo SE, Raffenne J, Varet H et al. Depletion of slow-cycling PDGFRα+ADAM12+ mesenchymal cells promotes antitumor immunity by restricting macrophage efferocytosis. Nature immunology. 2023.", "doi": "10.1038/s41590-023-01642-7", "pmcid": "PMC10602852", "url": "https://pubmed.ncbi.nlm.nih.gov/37798557/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37798557/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID37798557", "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" ], "favors_models": [], "evidence_class": "Strong", "system": "endogenous lineage tracing and stromal-cell depletion", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "ADAM12-marked slow mesenchymal cells acquire perivascular tumor-supporting states; depletion improves vascular/immune organization and reduces growth.", "what_it_does_not_show": "State and lineage restriction, tumor-induced remodeling and different cell populations constrain a unifying stromal hierarchy.", "confounders_present": [ "State and lineage restriction, tumor-induced remodeling and different cell populations constrain a unifying stromal 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": 25, "pmid": "11323675", "title": "IFNgamma and lymphocytes prevent primary tumour development and shape tumour immunogenicity.", "citation": "Shankaran V, Ikeda H, Bruce AT et al. IFNgamma and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature. 2001.", "doi": "10.1038/35074122", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/11323675/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/11323675/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID11323675", "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": "immunodeficient carcinogenesis and transplantation", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Lymphocyte/IFNgamma competence suppresses tumor development and selects tumor immunogenicity.", "what_it_does_not_show": "Host deficiency and carcinogen initiation are broad changes; immune editing is not immunity-only control of every malignant behavior.", "confounders_present": [ "Host deficiency and carcinogen initiation are broad changes; immune editing is not immunity-only control of every malignant behavior." ], "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": "18026089", "title": "Adaptive immunity maintains occult cancer in an equilibrium state.", "citation": "Koebel CM, Vermi W, Swann JB et al. Adaptive immunity maintains occult cancer in an equilibrium state. Nature. 2007.", "doi": "10.1038/nature06309", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/18026089/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/18026089/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID18026089", "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": "endogenous occult-tumor immune equilibrium", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Adaptive immune disruption releases occult carcinogen-induced tumors from prolonged equilibrium.", "what_it_does_not_show": "Transformed cells preexist; immune containment and eventual escape do not specify universal host primacy.", "confounders_present": [ "Transformed cells preexist; immune containment and eventual escape do not specify universal host primacy." ], "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": [ "Related immune-editing experimental platform to PMID11323675,22318521." ] }, { "n": 27, "pmid": "22318521", "title": "Cancer exome analysis reveals a T-cell-dependent mechanism of cancer immunoediting.", "citation": "Matsushita H, Vesely MD, Koboldt DC et al. Cancer exome analysis reveals a T-cell-dependent mechanism of cancer immunoediting. Nature. 2012.", "doi": "10.1038/nature10755", "pmcid": "PMC3874809", "url": "https://pubmed.ncbi.nlm.nih.gov/22318521/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/22318521/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID22318521", "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": "tumor antigen tracking and immune reconstitution", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Immune selection favors preexisting antigen-negative sarcoma clones with defined mutant antigen recognition.", "what_it_does_not_show": "Related immunoediting platform; genotype and immunity interact rather than forming separable universal hierarchies.", "confounders_present": [ "Related immunoediting platform; genotype and immunity interact rather than forming separable universal 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": [ "Related immune-editing experimental platform to PMID11323675,18026089." ] }, { "n": 28, "pmid": "15951814", "title": "A critical function for type I interferons in cancer immunoediting.", "citation": "Dunn GP, Bruce AT, Sheehan KC et al. A critical function for type I interferons in cancer immunoediting. Nature immunology. 2005.", "doi": "10.1038/ni1213", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/15951814/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/15951814/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID not supplied" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID15951814", "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" ], "favors_models": [], "evidence_class": "Strong", "system": "host/tumor IFN receptor and chimera contrasts", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Type I IFN dependence in host hematopoietic cells differs from IFNgamma tumor-target effects during tumor control.", "what_it_does_not_show": "Conditional cell targets, not all immune pathways; linked erratum contents unexamined.", "confounders_present": [ "Conditional cell targets, not all immune pathways; linked erratum contents unexamined." ], "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": "38815010", "title": "Germline-mediated immunoediting sculpts breast cancer subtypes and metastatic proclivity.", "citation": "Houlahan KE, Khan A, Greenwald NF et al. Germline-mediated immunoediting sculpts breast cancer subtypes and metastatic proclivity. Science (New York, N.Y.). 2024.", "doi": "10.1126/science.adh8697", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/38815010/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38815010/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "UpdateOf: PMID36993286" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID38815010", "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": "Weak", "system": "human germline/tumor immunoediting analysis", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Germline epitope repertoire associates with recurrent tumor alterations across 5870 lesions.", "what_it_does_not_show": "Computational selection and population associations are not randomized immune perturbation; earlier preprint is the same study.", "confounders_present": [ "Computational selection and population associations are not randomized immune perturbation; earlier preprint is the same study." ], "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": "30894752", "title": "Neoantigen-directed immune escape in lung cancer evolution.", "citation": "Rosenthal R, Cadieux EL, Salgado R et al. Neoantigen-directed immune escape in lung cancer evolution. Nature. 2019.", "doi": "10.1038/s41586-019-1032-7", "pmcid": "PMC6954100", "url": "https://pubmed.ncbi.nlm.nih.gov/30894752/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30894752/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID30894752", "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": "Moderate", "system": "human multiregion longitudinal clonal analysis", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "258 regions from 88 lung tumors reveal antigen-presentation loss and neoantigen expression/loss trajectories compatible with immune selection.", "what_it_does_not_show": "Observational clonal tracking infers selection but does not experimentally compare intrinsic and host primacy.", "confounders_present": [ "Observational clonal tracking infers selection but does not experimentally compare intrinsic and host primacy." ], "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": "16341007", "title": "VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche.", "citation": "Kaplan RN, Riba RD, Zacharoulis S et al. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature. 2005.", "doi": "10.1038/nature04186", "pmcid": "PMC2945882", "url": "https://pubmed.ncbi.nlm.nih.gov/16341007/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/16341007/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID16341007", "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" ], "favors_models": [], "evidence_class": "Moderate", "system": "metastatic niche recruitment/depletion/reconstitution", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "VEGFR1-positive progenitor perturbation and reconstitution alter premetastatic niche formation and metastasis in defined models.", "what_it_does_not_show": "Transplant/conditioned-medium and recruitment context; does not prove all spontaneous metastasis requires this niche.", "confounders_present": [ "Transplant/conditioned-medium and recruitment context; does not prove all spontaneous metastasis requires this niche." ], "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": "26524530", "title": "Tumour exosome integrins determine organotropic metastasis.", "citation": "Hoshino A, Costa-Silva B, Shen TL et al. Tumour exosome integrins determine organotropic metastasis. Nature. 2015.", "doi": "10.1038/nature15756", "pmcid": "PMC4788391", "url": "https://pubmed.ncbi.nlm.nih.gov/26524530/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26524530/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ExpressionOfConcernIn: PMID42557336" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID26524530", "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" ], "favors_models": [], "evidence_class": "Weak", "system": "historical exosome tropism experiments", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "The original report proposed organotropic exosomal integrins directing uptake and metastatic niche formation.", "what_it_does_not_show": "Nature expression of concern published 5 August 2026 identifies potentially overlapping images; excluded from positive load-bearing causal evidence. No raw-image audit or retraction claimed.", "confounders_present": [ "Nature expression of concern published 5 August 2026 identifies potentially overlapping images; excluded from positive load-bearing causal evidence. No raw-image audit or retraction claimed." ], "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": "23728425", "title": "The perivascular niche regulates breast tumour dormancy.", "citation": "Ghajar CM, Peinado H, Mori H et al. The perivascular niche regulates breast tumour dormancy. Nature cell biology. 2013.", "doi": "10.1038/ncb2767", "pmcid": "PMC3826912", "url": "https://pubmed.ncbi.nlm.nih.gov/23728425/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/23728425/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID23728425", "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": "Moderate", "system": "human organotypic and animal dormancy niches", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Stable endothelium/TSP1 sustains dormancy whereas sprouting niches and TGFbeta/periostin promote outgrowth.", "what_it_does_not_show": "Defined disseminated-cell contexts; unchanged genome cannot be presumed solely from similar cell lineage, and all malignant maintenance is broader.", "confounders_present": [ "Defined disseminated-cell contexts; unchanged genome cannot be presumed solely from similar cell lineage, and all malignant maintenance is broader." ], "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": "21706029", "title": "Breast cancer cells produce tenascin C as a metastatic niche component to colonize the lungs.", "citation": "Oskarsson T, Acharyya S, Zhang XH et al. Breast cancer cells produce tenascin C as a metastatic niche component to colonize the lungs. Nature medicine. 2011.", "doi": "10.1038/nm.2379", "pmcid": "PMC4020577", "url": "https://pubmed.ncbi.nlm.nih.gov/21706029/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/21706029/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID21706029", "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" ], "favors_models": [], "evidence_class": "Moderate", "system": "tumor/stromal tenascinC metastasis perturbation", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Tumor-derived tenascinC supports early metastatic colonization before host stromal supply becomes sufficient.", "what_it_does_not_show": "The niche effector initially originates from tumor cells; intrinsic/extrinsic boundary is mechanistically coupled.", "confounders_present": [ "The niche effector initially originates from tumor cells; intrinsic/extrinsic boundary is mechanistically coupled." ], "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": "17251932", "title": "Restoration of p53 function leads to tumour regression in vivo.", "citation": "Ventura A, Kirsch DG, McLaughlin ME et al. Restoration of p53 function leads to tumour regression in vivo. Nature. 2007.", "doi": "10.1038/nature05541", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/17251932/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/17251932/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID17251932", "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": "autochthonous p53 restoration", "decisive_perturbation": true, "endogenous": true, "direction": "contradicts", "what_it_shows": "Restoring p53 regresses established lymphomas and sarcomas through different apoptosis/senescence responses.", "what_it_does_not_show": "Tumor-type-dependent genetic restoration can remodel host effectors; not proof that every cancer is intrinsically dominant.", "confounders_present": [ "Tumor-type-dependent genetic restoration can remodel host effectors; not proof that every cancer is intrinsically dominant." ], "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": "17056717", "title": "Sustained regression of tumors upon MYC inactivation requires p53 or thrombospondin-1 to reverse the angiogenic switch.", "citation": "Giuriato S, Ryeom S, Fan AC et al. Sustained regression of tumors upon MYC inactivation requires p53 or thrombospondin-1 to reverse the angiogenic switch. Proceedings of the National Academy of Sciences of the United States of America. 2006.", "doi": "10.1073/pnas.0608017103", "pmcid": "PMC1637571", "url": "https://pubmed.ncbi.nlm.nih.gov/17056717/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/17056717/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID17056717", "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": "conditional MYC/p53/TSP1 tumor model", "decisive_perturbation": true, "endogenous": true, "direction": "contradicts", "what_it_shows": "p53-dependent TSP1 induction contributes to regression after MYC inactivation.", "what_it_does_not_show": "TSP1 alone does not suppress MYC-on growth; joint oncogene/host mechanism rather than either universal primacy.", "confounders_present": [ "TSP1 alone does not suppress MYC-on growth; joint oncogene/host mechanism rather than either universal primacy." ], "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": "17664422", "title": "Cellular senescence is an important mechanism of tumor regression upon c-Myc inactivation.", "citation": "Wu CH, van Riggelen J, Yetil A et al. Cellular senescence is an important mechanism of tumor regression upon c-Myc inactivation. Proceedings of the National Academy of Sciences of the United States of America. 2007.", "doi": "10.1073/pnas.0701953104", "pmcid": "PMC1941831", "url": "https://pubmed.ncbi.nlm.nih.gov/17664422/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/17664422/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID17664422", "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": "conditional oncogene and senescence-pathway perturbation", "decisive_perturbation": true, "endogenous": true, "direction": "contradicts", "what_it_shows": "p16/Rb/p53 senescence machinery influences durable regression after MYC withdrawal.", "what_it_does_not_show": "Cell-state and host effects cooperate; restricted transgenic programs do not define all sporadic cancers.", "confounders_present": [ "Cell-state and host effects cooperate; restricted transgenic programs do not define all sporadic cancers." ], "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": "12517816", "title": "Genomically complex lymphomas undergo sustained tumor regression upon MYC inactivation unless they acquire novel chromosomal translocations.", "citation": "Karlsson A, Giuriato S, Tang F et al. Genomically complex lymphomas undergo sustained tumor regression upon MYC inactivation unless they acquire novel chromosomal translocations. Blood. 2003.", "doi": "10.1182/blood-2002-10-3091", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/12517816/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/12517816/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID12517816", "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" ], "favors_models": [], "evidence_class": "Strong", "system": "conditional MYC complex lymphoma model", "decisive_perturbation": true, "endogenous": true, "direction": "contradicts", "what_it_shows": "MYC suppression regresses genetically complex lymphomas, with recurrent tumors acquiring replacement alterations.", "what_it_does_not_show": "Driver substitution after selection and transgene withdrawal differ from uniform endogenous human dependence.", "confounders_present": [ "Driver substitution after selection and transgene withdrawal differ from uniform endogenous human 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": 39, "pmid": "22232209", "title": "Oncogenic Kras is required for both the initiation and maintenance of pancreatic cancer in mice.", "citation": "Collins MA, Bednar F, Zhang Y et al. Oncogenic Kras is required for both the initiation and maintenance of pancreatic cancer in mice. The Journal of clinical investigation. 2012.", "doi": "10.1172/JCI59227", "pmcid": "PMC3266788", "url": "https://pubmed.ncbi.nlm.nih.gov/22232209/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/22232209/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID22232209", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:Publisher HTML paragraphs:paragraph71, 0:Publisher HTML paragraphs:paragraph73, 0:Publisher HTML paragraphs:paragraph74, 0:Publisher HTML paragraphs:paragraph75, 0:Publisher HTML paragraphs:paragraph76, 0:Publisher HTML paragraphs:paragraph80, 0:Publisher HTML paragraphs:paragraph83, 0:Publisher HTML paragraphs:paragraph84, 0:Publisher HTML paragraphs:paragraph85. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "autochthonous conditional KRAS pancreatic cancer", "decisive_perturbation": true, "endogenous": true, "direction": "contradicts", "what_it_shows": "Turning off oncogenic KRAS regresses MRI-confirmed invasive tumors within two weeks; selected mice remain tumor-free 23 weeks after withdrawal.", "what_it_does_not_show": "Transgenic expression, p53 background and cerulein injury restrict inference; small MRI cohort and simultaneous stromal remodeling do not establish opposite universal genetic primacy.", "confounders_present": [ "Transgenic expression, p53 background and cerulein injury restrict inference; small MRI cohort and simultaneous stromal remodeling do not establish opposite universal genetic primacy." ], "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": "21035406", "title": "CD4(+) T cells contribute to the remodeling of the microenvironment required for sustained tumor regression upon oncogene inactivation.", "citation": "Rakhra K, Bachireddy P, Zabuawala T et al. CD4(+) T cells contribute to the remodeling of the microenvironment required for sustained tumor regression upon oncogene inactivation. Cancer cell. 2010.", "doi": "10.1016/j.ccr.2010.10.002", "pmcid": "PMC2991103", "url": "https://pubmed.ncbi.nlm.nih.gov/21035406/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/21035406/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID not supplied" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID21035406", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph0, 1:Results:paragraph1, 1:Results:paragraph2, 1:Results:paragraph4, 1:Results:paragraph5, 1:Results:paragraph10, 1:Results:paragraph14, 1:Results:paragraph15, 1:Results:paragraph16, 1:Results:paragraph17. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "conditional MYC/BCRABL and host immune rescue", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "MYC-off apoptosis/arrest occurs across host immune states, but CD4 loss increases recurrence; CD4 transfer restores durable control and TSP-deficient effectors fail.", "what_it_does_not_show": "Initial and durable responses differ; immune bypass and intrinsic withdrawal jointly determine control. PubMed Comment label accompanies genuine original experiments; linked erratum unexamined.", "confounders_present": [ "Initial and durable responses differ; immune bypass and intrinsic withdrawal jointly determine control. PubMed Comment label accompanies genuine original experiments; linked erratum unexamined." ], "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": [ "Related conditional MYC platform to PMID17056717,17664422,26966191." ] }, { "n": 41, "pmid": "26966191", "title": "MYC regulates the antitumor immune response through CD47 and PD-L1.", "citation": "Casey SC, Tong L, Li Y et al. MYC regulates the antitumor immune response through CD47 and PD-L1. Science (New York, N.Y.). 2016.", "doi": "10.1126/science.aac9935", "pmcid": "PMC4940030", "url": "https://pubmed.ncbi.nlm.nih.gov/26966191/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26966191/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID27124464" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID26966191", "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": "MYC target and immune-ligand perturbation", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "MYC regulates CD47/PDL1 and enforced ligand expression impairs immune remodeling after MYC suppression.", "what_it_does_not_show": "Tumor genotype drives immune output; linked erratum27124464 metadata verified, contents unexamined.", "confounders_present": [ "Tumor genotype drives immune output; linked erratum27124464 metadata verified, contents unexamined." ], "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": "40901924", "title": "An allele-agnostic mutant-KRAS inhibitor suppresses tumor maintenance signals and reprograms tumor immunity in pancreatic cancer.", "citation": "McAndrews KM, Paradiso F, Stalnecker CA et al. An allele-agnostic mutant-KRAS inhibitor suppresses tumor maintenance signals and reprograms tumor immunity in pancreatic cancer. Science translational medicine. 2025.", "doi": "10.1126/scitranslmed.adt5511", "pmcid": "PMC12742855", "url": "https://pubmed.ncbi.nlm.nih.gov/40901924/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40901924/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID40901924", "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": "panKRAS preclinical autochthonous/PDX intervention", "decisive_perturbation": true, "endogenous": true, "direction": "contradicts", "what_it_shows": "PanKRAS inhibition suppresses diverse preclinical tumors and remodels tumor/microenvironment state; YAP-associated escape is interrogated.", "what_it_does_not_show": "Drug specificity and feedback matter; preclinical results are not patient efficacy or universal intrinsic dominance.", "confounders_present": [ "Drug specificity and feedback matter; preclinical results are not patient efficacy or universal intrinsic dominance." ], "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": 43, "pmid": "35815941", "title": "Metabolic requirement for GOT2 in pancreatic cancer depends on environmental context.", "citation": "Kerk SA, Lin L, Myers AL et al. Metabolic requirement for GOT2 in pancreatic cancer depends on environmental context. eLife. 2022.", "doi": "10.7554/eLife.73245", "pmcid": "PMC9328765", "url": "https://pubmed.ncbi.nlm.nih.gov/35815941/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35815941/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID35815941", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph14, 1:Results:paragraph17, 1:Results:paragraph23, 1:Results:paragraph27, 1:Results:paragraph34, 1:Results:paragraph36, 1:Results:paragraph40, 1:Results:paragraph55. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "GOT2 loss redox rescue and endogenous pancreatic models", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "GOT2 loss impairs culture but not tested in vivo growth; CAF pyruvate or cytosolic NADH oxidation rescues culture, whereas mitochondrial oxidation does not.", "what_it_does_not_show": "Confirmed MCT1 loss/inhibition fails to resensitize tumors in vivo, so CAF pyruvate is not established as the unique in vivo explanation; residual/alternative redox routes remain.", "confounders_present": [ "Confirmed MCT1 loss/inhibition fails to resensitize tumors in vivo, so CAF pyruvate is not established as the unique in vivo explanation; residual/alternative redox routes remain." ], "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": "35894778", "title": "A Cancer Cell-Intrinsic GOT2-PPARδ Axis Suppresses Antitumor Immunity.", "citation": "Abrego J, Sanford-Crane H, Oon C et al. A Cancer Cell-Intrinsic GOT2-PPARδ Axis Suppresses Antitumor Immunity. Cancer discovery. 2022.", "doi": "10.1158/2159-8290.CD-22-0661", "pmcid": "PMC9533011", "url": "https://pubmed.ncbi.nlm.nih.gov/35894778/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35894778/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID35894778", "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": "pancreatic GOT2 immune/metabolic perturbation", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "GOT2 supports PPARdelta-linked immune suppression beyond its proliferative metabolic role.", "what_it_does_not_show": "Different tumor/immune conditions and enzyme functions prevent treating context papers as a direct universal contradiction.", "confounders_present": [ "Different tumor/immune conditions and enzyme functions prevent treating context papers as a direct universal contradiction." ], "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": "15175435", "title": "Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer.", "citation": "Hurwitz H, Fehrenbacher L, Novotny W et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. The New England journal of medicine. 2004.", "doi": "10.1056/NEJMoa032691", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/15175435/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/15175435/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID15175435", "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" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Adding bevacizumab to IFL in 813 randomized metastatic colorectal patients increases median survival from 15.6 to 20.3 months, HR0.66.", "what_it_does_not_show": "Antiangiogenic/additive clinical benefit is not a matched comparison with extinguishing tumor drivers; delivery and vascular functions are coupled.", "confounders_present": [ "Antiangiogenic/additive clinical benefit is not a matched comparison with extinguishing tumor drivers; delivery and vascular functions are coupled." ], "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": "20525992", "title": "Improved survival with ipilimumab in patients with metastatic melanoma.", "citation": "Hodi FS, O'Day SJ, McDermott DF et al. Improved survival with ipilimumab in patients with metastatic melanoma. The New England journal of medicine. 2010.", "doi": "10.1056/NEJMoa1003466", "pmcid": "PMC3549297", "url": "https://pubmed.ncbi.nlm.nih.gov/20525992/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/20525992/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "ErratumIn: PMID not supplied" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID20525992", "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" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Ipilimumab improves median survival versus gp100 from 6.4 to 10.1 months in the defined advanced melanoma trial.", "what_it_does_not_show": "Selected HLA/treatment population and immune toxicity; survival benefit does not prove broad extrinsic dominance. Linked erratum contents unexamined.", "confounders_present": [ "Selected HLA/treatment population and immune toxicity; survival benefit does not prove broad extrinsic dominance. Linked erratum contents unexamined." ], "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": "26028407", "title": "Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer.", "citation": "Brahmer J, Reckamp KL, Baas P et al. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. The New England journal of medicine. 2015.", "doi": "10.1056/NEJMoa1504627", "pmcid": "PMC4681400", "url": "https://pubmed.ncbi.nlm.nih.gov/26028407/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26028407/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID26028407", "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" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "In 272 previously treated squamous NSCLC patients, nivolumab increases median survival from 6.0 to 9.2 months versus docetaxel, HR0.59.", "what_it_does_not_show": "Specific disease/treatment comparison; PDL1 nonprediction in this study does not mean genotype or tumor state is irrelevant.", "confounders_present": [ "Specific disease/treatment comparison; PDL1 nonprediction in this study does not mean genotype or tumor state is irrelevant." ], "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": "27718847", "title": "Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer.", "citation": "Reck M, Rodríguez-Abreu D, Robinson AG et al. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. The New England journal of medicine. 2016.", "doi": "10.1056/NEJMoa1606774", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/27718847/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/27718847/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID27718847", "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" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "In 305 PDL1-high NSCLC patients, pembrolizumab improves PFS from 6.0 to 10.3 months, HR0.50, versus chemotherapy.", "what_it_does_not_show": "Enrollment excludes sensitizing EGFR and ALK alterations and requires PDL1 at least 50 percent; cannot generalize to all genotypes.", "confounders_present": [ "Enrollment excludes sensitizing EGFR and ALK alterations and requires PDL1 at least 50 percent; cannot generalize to all genotypes." ], "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": "26027431", "title": "Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma.", "citation": "Larkin J, Chiarion-Sileni V, Gonzalez R et al. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. The New England journal of medicine. 2015.", "doi": "10.1056/NEJMoa1504030", "pmcid": "PMC5698905", "url": "https://pubmed.ncbi.nlm.nih.gov/26027431/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26027431/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "ErratumIn: PMID31442371" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "NCT01844505-CheckMate067", "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" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "CheckMate067 randomizes 945 melanoma patients; combination/nivolumab/ipilimumab median PFS is 11.5/6.9/2.9 months.", "what_it_does_not_show": "Initial report emphasizes PFS; later long-term survival is the same trial, not independent replication. Linked erratum31442371 contents unexamined.", "confounders_present": [ "Initial report emphasizes PFS; later long-term survival is the same trial, not independent replication. Linked erratum31442371 contents unexamined." ], "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": "39282897", "title": "Final, 10-Year Outcomes with Nivolumab plus Ipilimumab in Advanced Melanoma.", "citation": "Wolchok JD, Chiarion-Sileni V, Rutkowski P et al. Final, 10-Year Outcomes with Nivolumab plus Ipilimumab in Advanced Melanoma. The New England journal of medicine. 2025.", "doi": "10.1056/NEJMoa2407417", "pmcid": "PMC12080919", "url": "https://pubmed.ncbi.nlm.nih.gov/39282897/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39282897/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "NCT01844505-CheckMate067", "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" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Ten-year CheckMate067 follow-up reports median OS of 71.9/36.9/19.9 months for combination/nivolumab/ipilimumab.", "what_it_does_not_show": "Same NCT01844505 cohort as the 2015 report; online 2024 and journal issue 2025, not a new independent trial.", "confounders_present": [ "Same NCT01844505 cohort as the 2015 report; online 2024 and journal issue 2025, not a new independent trial." ], "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": "36774933", "title": "Adjuvant nivolumab plus ipilimumab versus placebo for localised renal cell carcinoma after nephrectomy (CheckMate 914): a double-blind, randomised, phase 3 trial.", "citation": "Motzer RJ, Russo P, Grünwald V et al. Adjuvant nivolumab plus ipilimumab versus placebo for localised renal cell carcinoma after nephrectomy (CheckMate 914): a double-blind, randomised, phase 3 trial. Lancet (London, England). 2023.", "doi": "10.1016/S0140-6736(22)02574-0", "pmcid": "PMC10259621", "url": "https://pubmed.ncbi.nlm.nih.gov/36774933/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36774933/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID36774933", "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" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "null", "what_it_shows": "CheckMate914 part A in 816 randomized high-risk resected renal patients finds no significant DFS gain, HR0.92, CI0.71–1.19, p0.53.", "what_it_does_not_show": "Specific adjuvant regimen and 32 versus 2 percent toxicity discontinuation; null is not proof immunity never controls RCC.", "confounders_present": [ "Specific adjuvant regimen and 32 versus 2 percent toxicity discontinuation; null is not proof immunity never controls RCC." ], "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": "24552317", "title": "A randomized trial of bevacizumab for newly diagnosed glioblastoma.", "citation": "Gilbert MR, Dignam JJ, Armstrong TS et al. A randomized trial of bevacizumab for newly diagnosed glioblastoma. The New England journal of medicine. 2014.", "doi": "10.1056/NEJMoa1308573", "pmcid": "PMC4201043", "url": "https://pubmed.ncbi.nlm.nih.gov/24552317/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/24552317/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID24552317", "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" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "null", "what_it_shows": "RTOG0825 randomizes 637 of 978 registered glioblastoma patients; bevacizumab yields OS15.7 versus16.1 months and worse selected cognitive/QoL outcomes.", "what_it_does_not_show": "PFS10.7 versus7.3 months does not meet preset improvement; vascular imaging/response changes are not survival proof.", "confounders_present": [ "PFS10.7 versus7.3 months does not meet preset improvement; vascular imaging/response changes are not survival proof." ], "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": "24552318", "title": "Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma.", "citation": "Chinot OL, Wick W, Mason W et al. Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. The New England journal of medicine. 2014.", "doi": "10.1056/NEJMoa1308345", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/24552318/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/24552318/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID24552318", "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" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "null", "what_it_shows": "AVAglio in 921 patients improves PFS10.6 versus6.2 months, HR0.64, with no significant OS benefit, p0.10.", "what_it_does_not_show": "QoL instruments/protocol differ from RTOG0825; do not collapse different QoL findings or infer absent vascular biology.", "confounders_present": [ "QoL instruments/protocol differ from RTOG0825; do not collapse different QoL findings or infer absent vascular biology." ], "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": "32706635", "title": "Randomized Phase III Trial of Pegvorhyaluronidase Alfa With Nab-Paclitaxel Plus Gemcitabine for Patients With Hyaluronan-High Metastatic Pancreatic Adenocarcinoma.", "citation": "Van Cutsem E, Tempero MA, Sigal D et al. Randomized Phase III Trial of Pegvorhyaluronidase Alfa With Nab-Paclitaxel Plus Gemcitabine for Patients With Hyaluronan-High Metastatic Pancreatic Adenocarcinoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2020.", "doi": "10.1200/JCO.20.00590", "pmcid": "PMC7499614", "url": "https://pubmed.ncbi.nlm.nih.gov/32706635/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32706635/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID32706635", "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" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "null", "what_it_shows": "HALO301 has 494 randomized and 492 analysis patients; hyaluronan targeting yields OS11.2 versus11.5 months, HR1.00, and equal PFS7.1 months despite greater response.", "what_it_does_not_show": "Hyaluronan-high selected disease, toxicity and drug regimen; response is not survival and null does not negate all stromal contributions.", "confounders_present": [ "Hyaluronan-high selected disease, toxicity and drug regimen; response is not survival and null does not negate all stromal contributions." ], "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": "29867230", "title": "Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma.", "citation": "McDermott DF, Huseni MA, Atkins MB et al. Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma. Nature medicine. 2018.", "doi": "10.1038/s41591-018-0053-3", "pmcid": "PMC6721896", "url": "https://pubmed.ncbi.nlm.nih.gov/29867230/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29867230/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "ErratumIn: PMID30291359" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID29867230", "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" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "null", "what_it_shows": "IMmotion150 phase2 randomizes 305 RCC patients; combination versus sunitinib ITT PFS HR1.00, CI0.69–1.45, with immune/angiogenic signatures.", "what_it_does_not_show": "TMB is not associated with PFS in this study; biomarker signatures do not prove layer primacy. Linked correction30291359 contents unexamined.", "confounders_present": [ "TMB is not associated with PFS in this study; biomarker signatures do not prove layer primacy. Linked correction30291359 contents unexamined." ], "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": "26645196", "title": "Loss of PTEN Promotes Resistance to T Cell-Mediated Immunotherapy.", "citation": "Peng W, Chen JQ, Liu C et al. Loss of PTEN Promotes Resistance to T Cell-Mediated Immunotherapy. Cancer discovery. 2016.", "doi": "10.1158/2159-8290.CD-15-0283", "pmcid": "PMC4744499", "url": "https://pubmed.ncbi.nlm.nih.gov/26645196/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26645196/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID26645196", "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": "tumor PTEN perturbation and immune therapy models", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "PTEN loss alters cytokine/autophagy programs, T-cell access and therapy response; PI3Kbeta intervention improves immune control.", "what_it_does_not_show": "Intrinsic genetic and host pathways are causally coupled, not separable universal dominant compartments.", "confounders_present": [ "Intrinsic genetic and host pathways are causally coupled, not separable universal dominant compartments." ], "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": "27903500", "title": "Primary Resistance to PD-1 Blockade Mediated by JAK1/2 Mutations.", "citation": "Shin DS, Zaretsky JM, Escuin-Ordinas H et al. Primary Resistance to PD-1 Blockade Mediated by JAK1/2 Mutations. Cancer discovery. 2017.", "doi": "10.1158/2159-8290.CD-16-1223", "pmcid": "PMC5296316", "url": "https://pubmed.ncbi.nlm.nih.gov/27903500/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/27903500/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID27903500", "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": "Moderate", "system": "human rare resistance plus cell functional analysis", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "JAK1/2 alterations in rare high-mutational-burden nonresponders impair interferon-linked immune response.", "what_it_does_not_show": "One of 23 melanoma and one of 16 colorectal patients; rare cases and cell assays do not establish population-wide primacy.", "confounders_present": [ "One of 23 melanoma and one of 16 colorectal patients; rare cases and cell assays do not establish population-wide primacy." ], "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": "27433843", "title": "Mutations Associated with Acquired Resistance to PD-1 Blockade in Melanoma.", "citation": "Zaretsky JM, Garcia-Diaz A, Shin DS et al. Mutations Associated with Acquired Resistance to PD-1 Blockade in Melanoma. The New England journal of medicine. 2016.", "doi": "10.1056/NEJMoa1604958", "pmcid": "PMC5007206", "url": "https://pubmed.ncbi.nlm.nih.gov/27433843/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/27433843/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID27433843", "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": "Moderate", "system": "paired human biopsies and functional resistance", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Four acquired-resistance cases reveal JAK1/2 lesions in two and B2M loss in one with altered antigen/IFN response.", "what_it_does_not_show": "Small selected series; antigen presentation and IFN mechanisms differ and do not cover all immune escape.", "confounders_present": [ "Small selected series; antigen presentation and IFN mechanisms differ and do not cover all immune escape." ], "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": "32467343", "title": "Overcoming Genetically Based Resistance Mechanisms to PD-1 Blockade.", "citation": "Torrejon DY, Abril-Rodriguez G, Champhekar AS et al. Overcoming Genetically Based Resistance Mechanisms to PD-1 Blockade. Cancer discovery. 2020.", "doi": "10.1158/2159-8290.CD-19-1409", "pmcid": "PMC7416458", "url": "https://pubmed.ncbi.nlm.nih.gov/32467343/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32467343/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID32467343", "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": "Moderate", "system": "engineered resistance and innate-immune rescue", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "JAK or B2M disruption produces checkpoint resistance; TLR9/PD1 or CD4/NK/IL2 routes restore selected responses.", "what_it_does_not_show": "Genetically imposed immune escape can be bypassed, opposing immutable genetic dominance; engineered models do not establish universal immune primacy.", "confounders_present": [ "Genetically imposed immune escape can be bypassed, opposing immutable genetic dominance; engineered models do not establish universal immune primacy." ], "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": 60, "pmid": "19249681", "title": "Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis.", "citation": "Ebos JM, Lee CR, Cruz-Munoz W et al. Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer cell. 2009.", "doi": "10.1016/j.ccr.2009.01.021", "pmcid": "PMC4540346", "url": "https://pubmed.ncbi.nlm.nih.gov/19249681/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/19249681/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID19249681", "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": "Moderate", "system": "antiangiogenic timing and metastatic mouse models", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "Short VEGF-pathway inhibition/preconditioning can accelerate metastatic growth while suppressing primary tumors.", "what_it_does_not_show": "Pretreatment, intravenous/resection context and short schedule cannot be equated with prolonged human therapy effects.", "confounders_present": [ "Pretreatment, intravenous/resection context and short schedule cannot be equated with prolonged human therapy effects." ], "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": "19249680", "title": "Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis.", "citation": "Pàez-Ribes M, Allen E, Hudock J et al. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer cell. 2009.", "doi": "10.1016/j.ccr.2009.01.027", "pmcid": "PMC2874829", "url": "https://pubmed.ncbi.nlm.nih.gov/19249680/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/19249680/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID19249680", "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": "pharmacologic/genetic angiogenesis mouse contrasts", "decisive_perturbation": true, "endogenous": true, "direction": "contradicts", "what_it_shows": "VEGF-targeting reduces primary growth yet increases local invasion/metastasis in selected settings.", "what_it_does_not_show": "Stage, hypoxia and vessel mechanism can change sign; no claim that all antiangiogenic clinical treatment increases metastasis.", "confounders_present": [ "Stage, hypoxia and vessel mechanism can change sign; no claim that all antiangiogenic clinical treatment increases metastasis." ], "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": "41533516", "title": "In situ multi-modal characterization of pancreatic cancer reveals tumor cell identity as a defining factor of the surrounding microenvironment.", "citation": "Lyubetskaya A, Rabe B, Kavran A et al. In situ multi-modal characterization of pancreatic cancer reveals tumor cell identity as a defining factor of the surrounding microenvironment. Cell reports. 2026.", "doi": "10.1016/j.celrep.2025.116827", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/41533516/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/41533516/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID41533516", "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": "Weak", "system": "human pretreatment spatial/single-cell analysis", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Tumor identity and malignant programs associate with spatial immune/stromal neighborhoods in untreated pancreatic ductal adenocarcinoma from 39 patients.", "what_it_does_not_show": "Before-cutoff 2026 report; observational spatial association does not identify directional causal dominance.", "confounders_present": [ "Before-cutoff 2026 report; observational spatial association does not identify directional causal dominance." ], "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": 63, "pmid": "41121153", "title": "ITGB5-mediated biomechanical regulation in pancreatic ductal adenocarcinoma stroma impacts tumor progression and prognosis.", "citation": "Yang A, Gu C, Liu Y et al. ITGB5-mediated biomechanical regulation in pancreatic ductal adenocarcinoma stroma impacts tumor progression and prognosis. Journal of translational medicine. 2025.", "doi": "10.1186/s12967-025-07119-5", "pmcid": "PMC12542423", "url": "https://pubmed.ncbi.nlm.nih.gov/41121153/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/41121153/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID41121153", "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" ], "favors_models": [], "evidence_class": "Moderate", "system": "CAF ITGB5/biophysical perturbation and clinical association", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "ITGB5-positive CAFs alter stromal stiffness and pancreatic ductal adenocarcinoma progression in experimental models with clinical association.", "what_it_does_not_show": "Prognostic/registration statements in the abstract are not independently verified clinical validation; binding/signaling and matrix state vary together.", "confounders_present": [ "Prognostic/registration statements in the abstract are not independently verified clinical validation; binding/signaling and matrix state vary together." ], "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": "39441902", "title": "Stromal reprogramming overcomes resistance to RAS-MAPK inhibition to improve pancreas cancer responses to cytotoxic and immune therapy.", "citation": "Liu X, Baer JM, Stone ML et al. Stromal reprogramming overcomes resistance to RAS-MAPK inhibition to improve pancreas cancer responses to cytotoxic and immune therapy. Science translational medicine. 2024.", "doi": "10.1126/scitranslmed.ado2402", "pmcid": "PMC12376167", "url": "https://pubmed.ncbi.nlm.nih.gov/39441902/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39441902/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID39441902", "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": "pancreatic RAFMEK/FAK combination models", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Stromal FGF1 maintains tumor MYC under RAF/MEK blockade; adding FAK inhibition enables regression in defined pancreatic models.", "what_it_does_not_show": "Joint pathway treatment reinforces tumor/host feedback; a 2024 trial statement does not establish current recruitment or clinical efficacy.", "confounders_present": [ "Joint pathway treatment reinforces tumor/host feedback; a 2024 trial statement does not establish current recruitment or clinical efficacy." ], "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": 67, "verified": 67, "unverified": 0, "contradicted": 0, "note": "Verified attribution is distinct from mechanism truth or complete body access." }, "factual_issues_found": [], "cap_rules_applied": [ { "subclaim_id": "SC2", "cap": "Γ", "cap_source": "rubric", "triggered": true, "trigger_text_quoted": "Mechanistically plausible cell culture or transplantation-linked models without endogenous in vivo dependency cap at Γ.", "specific_trigger": "Γ: scoped host-dependent resistance and tissue-humanization models support primacy as a mechanistic possibility. Paired evidence also shows continued intrinsic dependencies and joint immune/oncogene requirements. The registered general dominance claim lacks convergent endogenous factorial comparisons; influence cannot substitute for primacy.", "resulting_ceiling": "Γ" } ], "cap_precedence_resolutions": [ { "collision": "Perturbation in a defined setting versus broader inference", "subclaim_scope_cap_binds_on": "Tumor-microenvironment factors are primary drivers of malignant maintenance and progression, dominating cell-autonomous genetic and epigenetic drivers.", "subclaim_scope_threshold_binds_on": "The precise experimentally tested subclaim scope", "resolution": "Endogenous genetic/immune perturbations and clinical survival effects cross contribution and reach Η for SC1 when assembled across independent failure modes. Xenograft limits bind broad SC2 dominance, not the whole causal TME literature. Quail resistance/retransplantation supports a restricted environmental state dependence, while endogenous KRAS and MYC/CD4 tests show why it cannot substitute for general primacy. The assembled SC1 convergence is not re-capped by one culture study.", "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": "PMID10519415, PMID15051869, PMID15882617, PMID19931152, PMID21729786, PMID26676755, PMID31406163, PMID30366930, PMID35348629, PMID24856585, PMID24856586, PMID25024225, PMID33667385, PMID33495315, PMID24277834, PMID29443960, PMID29443964, PMID24056773, PMID27199435, PMID21822305, PMID17114237, PMID37798557, PMID11323675, PMID18026089, PMID22318521, PMID15951814, PMID16341007, PMID23728425, PMID21706029, PMID17251932, PMID17056717, PMID17664422, PMID22232209, PMID21035406, PMID26966191, PMID40901924, PMID35815941, PMID35894778, PMID15175435, PMID20525992, PMID26028407, PMID27718847, PMID26027431, PMID39282897, PMID36774933, PMID24552317, PMID24552318, PMID32706635, PMID29867230, PMID26645196, PMID27903500, PMID27433843, PMID32467343, PMID19249681, PMID19249680, PMID41121153, PMID39441902", "gamma_hard_rules_triggered": [], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "yes", "perturbation_result_note": "Η: endogenous compartment-specific loss, immune restoration, relapse/resistance tests and independent clinical survival interventions establish causal TME influence within explicitly defined compartments/settings. They reject the claim that all TME change is reactive; they do not make every stromal factor rate-limiting.", "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": "no", "qualifying_evidence_citation": "PMID10519415, PMID15051869, PMID19931152, PMID26676755, PMID31406163, PMID35348629, PMID24856585, PMID24856586, PMID25024225, PMID33667385, PMID33495315, PMID24277834, PMID29443960, PMID29443964, PMID27199435, PMID11323675, PMID18026089, PMID22318521, PMID23728425, PMID17251932, PMID17056717, PMID17664422, PMID12517816, PMID22232209, PMID21035406, PMID26966191, PMID40901924, PMID35815941, PMID35894778, PMID26645196, PMID27903500, PMID27433843, PMID32467343, PMID19249681, PMID19249680, PMID39441902", "gamma_hard_rules_triggered": [ "Xenograft sufficiency without lineage-resolved exclusion of preexisting malignant cells cannot carry general dominance.", "Host-dependent resistance does not establish the same hierarchy for untreated maintenance across genotypes/stages." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "Γ: scoped host-dependent resistance and tissue-humanization models support primacy as a mechanistic possibility. Paired evidence also shows continued intrinsic dependencies and joint immune/oncogene requirements. The registered general dominance claim lacks convergent endogenous factorial comparisons; influence cannot substitute for primacy.", "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": [ "[1] Carcinoma-associated versus normal fibroblasts promote tumor growth from initiated, nontumorigenic prostate epithelium.", "[2] Growth-factor-modified stroma produces malignant outgrowth in 16/18 grafts from one donor; adding normal fibroblasts prevents abnormal outgrowth.", "[3] CAFs from human breast cancers promote growth through SDF1/CXCL12-associated angiogenic recruitment and epithelial CXCR4 signaling.", "[4] LOX-linked matrix crosslinking promotes integrin signaling and invasion; blocking crosslinking reduces fibrosis, tumor incidence and progression.", "[5] Fibroblast caveolin1 influences matrix remodeling, stiffness and invasion with Rho/p190 signaling contrasts.", "[6] A wound/fibrotic environment promotes squamous carcinogenesis with TGFbeta/LOX/integrin pathway contrasts.", "[7] Tumor gain-of-function p53 educates fibroblasts into a perlecan-rich niche supporting invasion and therapy resistance.", "[9] IL1/LIF/JAKSTAT promotes inflammatory CAFs while TGFbeta suppresses IL1R1 and favors myofibroblastic states.", "[10] FAP-positive CAF depletion improves survival whereas alphaSMA-positive depletion worsens it; alphaSMA-specific IL6 loss improves gemcitabine response.", "[11] SHH loss reduces stroma but median survival falls from 6.17 to 3.61 months and gross metastasis rises from 15.3 to 43.4 percent; VEGFR2 blockade selectively rescues the stroma-low setting.", "[12] Approximately 80 percent myofibroblast depletion accelerates aggressive disease and shortens survival despite lower tumor weight; antiCTLA4 increases median survival to 65 versus control 47 days.", "[13] Hedgehog inhibition accelerates pancreatic disease whereas pathway activation expands stroma and reduces epithelial proliferation.", "[14] AlphaSMA-specific Col1 deletion reduces fibrillar collagen/stiffness and accelerates PDAC; CXCR2/CCR2 blockade restores survival toward control.", "[15] SHH overexpression promotes growth and Smo inhibition impairs it while shifting myCAF/iCAF and immune composition.", "[16] FAP-cell and CXCL12 contrasts identify immune exclusion; AMD3100 plus antiPDL1 rapidly removes tumor cells in a defined pancreatic model.", "[17] TGFbeta-rich stroma associates with immune exclusion; combined TGFbeta/PDL1 blockade restores penetration and regression in mouse tumors.", "[18] TGFbeta blockade prevents metastasis and enables checkpoint control of established lesions in low-mutational-burden driver-mutant CRC.", "[19] CSF1R inhibition regresses glioma and prolongs survival through macrophage-state alteration.", "[20] Continued CSF1R blockade produces rebound in 56 percent; rebound cells regain sensitivity in naive hosts, and IGF1R plus CSF1R inhibition extends recurrent-tumor median survival from 13 to 63 days.", "[22] CSF1 deficiency reduces macrophages, angiogenic switching and total pancreatic neuroendocrine tumor burden.", "[23] Macrophage recruitment promotes an angiogenic switch; blocked infiltration delays progression and local restoration restores vascular effects.", "[24] ADAM12-marked slow mesenchymal cells acquire perivascular tumor-supporting states; depletion improves vascular/immune organization and reduces growth.", "[25] Lymphocyte/IFNgamma competence suppresses tumor development and selects tumor immunogenicity.", "[26] Adaptive immune disruption releases occult carcinogen-induced tumors from prolonged equilibrium.", "[27] Immune selection favors preexisting antigen-negative sarcoma clones with defined mutant antigen recognition.", "[28] Type I IFN dependence in host hematopoietic cells differs from IFNgamma tumor-target effects during tumor control.", "[31] VEGFR1-positive progenitor perturbation and reconstitution alter premetastatic niche formation and metastasis in defined models.", "[33] Stable endothelium/TSP1 sustains dormancy whereas sprouting niches and TGFbeta/periostin promote outgrowth.", "[34] Tumor-derived tenascinC supports early metastatic colonization before host stromal supply becomes sufficient.", "[35] Restoring p53 regresses established lymphomas and sarcomas through different apoptosis/senescence responses.", "[36] p53-dependent TSP1 induction contributes to regression after MYC inactivation.", "[37] p16/Rb/p53 senescence machinery influences durable regression after MYC withdrawal.", "[39] Turning off oncogenic KRAS regresses MRI-confirmed invasive tumors within two weeks; selected mice remain tumor-free 23 weeks after withdrawal.", "[40] MYC-off apoptosis/arrest occurs across host immune states, but CD4 loss increases recurrence; CD4 transfer restores durable control and TSP-deficient effectors fail.", "[41] MYC regulates CD47/PDL1 and enforced ligand expression impairs immune remodeling after MYC suppression.", "[42] PanKRAS inhibition suppresses diverse preclinical tumors and remodels tumor/microenvironment state; YAP-associated escape is interrogated.", "[43] GOT2 loss impairs culture but not tested in vivo growth; CAF pyruvate or cytosolic NADH oxidation rescues culture, whereas mitochondrial oxidation does not.", "[44] GOT2 supports PPARdelta-linked immune suppression beyond its proliferative metabolic role.", "[45] Adding bevacizumab to IFL in 813 randomized metastatic colorectal patients increases median survival from 15.6 to 20.3 months, HR0.66.", "[46] Ipilimumab improves median survival versus gp100 from 6.4 to 10.1 months in the defined advanced melanoma trial.", "[47] In 272 previously treated squamous NSCLC patients, nivolumab increases median survival from 6.0 to 9.2 months versus docetaxel, HR0.59.", "[48] In 305 PDL1-high NSCLC patients, pembrolizumab improves PFS from 6.0 to 10.3 months, HR0.50, versus chemotherapy.", "[49] CheckMate067 randomizes 945 melanoma patients; combination/nivolumab/ipilimumab median PFS is 11.5/6.9/2.9 months.", "[50] Ten-year CheckMate067 follow-up reports median OS of 71.9/36.9/19.9 months for combination/nivolumab/ipilimumab.", "[51] CheckMate914 part A in 816 randomized high-risk resected renal patients finds no significant DFS gain, HR0.92, CI0.71–1.19, p0.53.", "[52] RTOG0825 randomizes 637 of 978 registered glioblastoma patients; bevacizumab yields OS15.7 versus16.1 months and worse selected cognitive/QoL outcomes.", "[53] AVAglio in 921 patients improves PFS10.6 versus6.2 months, HR0.64, with no significant OS benefit, p0.10.", "[54] HALO301 has 494 randomized and 492 analysis patients; hyaluronan targeting yields OS11.2 versus11.5 months, HR1.00, and equal PFS7.1 months despite greater response.", "[55] IMmotion150 phase2 randomizes 305 RCC patients; combination versus sunitinib ITT PFS HR1.00, CI0.69–1.45, with immune/angiogenic signatures.", "[56] PTEN loss alters cytokine/autophagy programs, T-cell access and therapy response; PI3Kbeta intervention improves immune control.", "[57] JAK1/2 alterations in rare high-mutational-burden nonresponders impair interferon-linked immune response.", "[58] Four acquired-resistance cases reveal JAK1/2 lesions in two and B2M loss in one with altered antigen/IFN response.", "[59] JAK or B2M disruption produces checkpoint resistance; TLR9/PD1 or CD4/NK/IL2 routes restore selected responses.", "[60] Short VEGF-pathway inhibition/preconditioning can accelerate metastatic growth while suppressing primary tumors.", "[61] VEGF-targeting reduces primary growth yet increases local invasion/metastasis in selected settings.", "[63] ITGB5-positive CAFs alter stromal stiffness and pancreatic ductal adenocarcinoma progression in experimental models with clinical association.", "[64] Stromal FGF1 maintains tumor MYC under RAF/MEK blockade; adding FAK inhibition enables regression in defined pancreatic models." ], "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": [ "[1] Carcinoma-associated versus normal fibroblasts promote tumor growth from initiated, nontumorigenic prostate epithelium.", "[2] Growth-factor-modified stroma produces malignant outgrowth in 16/18 grafts from one donor; adding normal fibroblasts prevents abnormal outgrowth.", "[3] CAFs from human breast cancers promote growth through SDF1/CXCL12-associated angiogenic recruitment and epithelial CXCR4 signaling.", "[4] LOX-linked matrix crosslinking promotes integrin signaling and invasion; blocking crosslinking reduces fibrosis, tumor incidence and progression.", "[5] Fibroblast caveolin1 influences matrix remodeling, stiffness and invasion with Rho/p190 signaling contrasts.", "[6] A wound/fibrotic environment promotes squamous carcinogenesis with TGFbeta/LOX/integrin pathway contrasts.", "[7] Tumor gain-of-function p53 educates fibroblasts into a perlecan-rich niche supporting invasion and therapy resistance.", "[9] IL1/LIF/JAKSTAT promotes inflammatory CAFs while TGFbeta suppresses IL1R1 and favors myofibroblastic states.", "[10] FAP-positive CAF depletion improves survival whereas alphaSMA-positive depletion worsens it; alphaSMA-specific IL6 loss improves gemcitabine response.", "[11] SHH loss reduces stroma but median survival falls from 6.17 to 3.61 months and gross metastasis rises from 15.3 to 43.4 percent; VEGFR2 blockade selectively rescues the stroma-low setting.", "[12] Approximately 80 percent myofibroblast depletion accelerates aggressive disease and shortens survival despite lower tumor weight; antiCTLA4 increases median survival to 65 versus control 47 days.", "[13] Hedgehog inhibition accelerates pancreatic disease whereas pathway activation expands stroma and reduces epithelial proliferation.", "[14] AlphaSMA-specific Col1 deletion reduces fibrillar collagen/stiffness and accelerates PDAC; CXCR2/CCR2 blockade restores survival toward control.", "[15] SHH overexpression promotes growth and Smo inhibition impairs it while shifting myCAF/iCAF and immune composition.", "[16] FAP-cell and CXCL12 contrasts identify immune exclusion; AMD3100 plus antiPDL1 rapidly removes tumor cells in a defined pancreatic model.", "[17] TGFbeta-rich stroma associates with immune exclusion; combined TGFbeta/PDL1 blockade restores penetration and regression in mouse tumors.", "[18] TGFbeta blockade prevents metastasis and enables checkpoint control of established lesions in low-mutational-burden driver-mutant CRC.", "[19] CSF1R inhibition regresses glioma and prolongs survival through macrophage-state alteration.", "[20] Continued CSF1R blockade produces rebound in 56 percent; rebound cells regain sensitivity in naive hosts, and IGF1R plus CSF1R inhibition extends recurrent-tumor median survival from 13 to 63 days.", "[22] CSF1 deficiency reduces macrophages, angiogenic switching and total pancreatic neuroendocrine tumor burden.", "[23] Macrophage recruitment promotes an angiogenic switch; blocked infiltration delays progression and local restoration restores vascular effects.", "[24] ADAM12-marked slow mesenchymal cells acquire perivascular tumor-supporting states; depletion improves vascular/immune organization and reduces growth.", "[25] Lymphocyte/IFNgamma competence suppresses tumor development and selects tumor immunogenicity.", "[26] Adaptive immune disruption releases occult carcinogen-induced tumors from prolonged equilibrium.", "[27] Immune selection favors preexisting antigen-negative sarcoma clones with defined mutant antigen recognition.", "[28] Type I IFN dependence in host hematopoietic cells differs from IFNgamma tumor-target effects during tumor control.", "[31] VEGFR1-positive progenitor perturbation and reconstitution alter premetastatic niche formation and metastasis in defined models.", "[33] Stable endothelium/TSP1 sustains dormancy whereas sprouting niches and TGFbeta/periostin promote outgrowth.", "[34] Tumor-derived tenascinC supports early metastatic colonization before host stromal supply becomes sufficient.", "[35] Restoring p53 regresses established lymphomas and sarcomas through different apoptosis/senescence responses.", "[36] p53-dependent TSP1 induction contributes to regression after MYC inactivation.", "[37] p16/Rb/p53 senescence machinery influences durable regression after MYC withdrawal.", "[39] Turning off oncogenic KRAS regresses MRI-confirmed invasive tumors within two weeks; selected mice remain tumor-free 23 weeks after withdrawal.", "[40] MYC-off apoptosis/arrest occurs across host immune states, but CD4 loss increases recurrence; CD4 transfer restores durable control and TSP-deficient effectors fail.", "[41] MYC regulates CD47/PDL1 and enforced ligand expression impairs immune remodeling after MYC suppression.", "[42] PanKRAS inhibition suppresses diverse preclinical tumors and remodels tumor/microenvironment state; YAP-associated escape is interrogated.", "[43] GOT2 loss impairs culture but not tested in vivo growth; CAF pyruvate or cytosolic NADH oxidation rescues culture, whereas mitochondrial oxidation does not.", "[44] GOT2 supports PPARdelta-linked immune suppression beyond its proliferative metabolic role.", "[45] Adding bevacizumab to IFL in 813 randomized metastatic colorectal patients increases median survival from 15.6 to 20.3 months, HR0.66.", "[46] Ipilimumab improves median survival versus gp100 from 6.4 to 10.1 months in the defined advanced melanoma trial.", "[47] In 272 previously treated squamous NSCLC patients, nivolumab increases median survival from 6.0 to 9.2 months versus docetaxel, HR0.59.", "[48] In 305 PDL1-high NSCLC patients, pembrolizumab improves PFS from 6.0 to 10.3 months, HR0.50, versus chemotherapy.", "[49] CheckMate067 randomizes 945 melanoma patients; combination/nivolumab/ipilimumab median PFS is 11.5/6.9/2.9 months.", "[50] Ten-year CheckMate067 follow-up reports median OS of 71.9/36.9/19.9 months for combination/nivolumab/ipilimumab.", "[51] CheckMate914 part A in 816 randomized high-risk resected renal patients finds no significant DFS gain, HR0.92, CI0.71–1.19, p0.53.", "[52] RTOG0825 randomizes 637 of 978 registered glioblastoma patients; bevacizumab yields OS15.7 versus16.1 months and worse selected cognitive/QoL outcomes.", "[53] AVAglio in 921 patients improves PFS10.6 versus6.2 months, HR0.64, with no significant OS benefit, p0.10.", "[54] HALO301 has 494 randomized and 492 analysis patients; hyaluronan targeting yields OS11.2 versus11.5 months, HR1.00, and equal PFS7.1 months despite greater response.", "[55] IMmotion150 phase2 randomizes 305 RCC patients; combination versus sunitinib ITT PFS HR1.00, CI0.69–1.45, with immune/angiogenic signatures.", "[56] PTEN loss alters cytokine/autophagy programs, T-cell access and therapy response; PI3Kbeta intervention improves immune control.", "[57] JAK1/2 alterations in rare high-mutational-burden nonresponders impair interferon-linked immune response.", "[58] Four acquired-resistance cases reveal JAK1/2 lesions in two and B2M loss in one with altered antigen/IFN response.", "[59] JAK or B2M disruption produces checkpoint resistance; TLR9/PD1 or CD4/NK/IL2 routes restore selected responses.", "[60] Short VEGF-pathway inhibition/preconditioning can accelerate metastatic growth while suppressing primary tumors.", "[61] VEGF-targeting reduces primary growth yet increases local invasion/metastasis in selected settings.", "[63] ITGB5-positive CAFs alter stromal stiffness and pancreatic ductal adenocarcinoma progression in experimental models with clinical association.", "[64] Stromal FGF1 maintains tumor MYC under RAF/MEK blockade; adding FAK inhibition enables regression in defined pancreatic models." ], "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": [ "[1] Carcinoma-associated versus normal fibroblasts promote tumor growth from initiated, nontumorigenic prostate epithelium.", "[2] Growth-factor-modified stroma produces malignant outgrowth in 16/18 grafts from one donor; adding normal fibroblasts prevents abnormal outgrowth.", "[3] CAFs from human breast cancers promote growth through SDF1/CXCL12-associated angiogenic recruitment and epithelial CXCR4 signaling.", "[4] LOX-linked matrix crosslinking promotes integrin signaling and invasion; blocking crosslinking reduces fibrosis, tumor incidence and progression.", "[5] Fibroblast caveolin1 influences matrix remodeling, stiffness and invasion with Rho/p190 signaling contrasts.", "[6] A wound/fibrotic environment promotes squamous carcinogenesis with TGFbeta/LOX/integrin pathway contrasts.", "[7] Tumor gain-of-function p53 educates fibroblasts into a perlecan-rich niche supporting invasion and therapy resistance.", "[9] IL1/LIF/JAKSTAT promotes inflammatory CAFs while TGFbeta suppresses IL1R1 and favors myofibroblastic states.", "[10] FAP-positive CAF depletion improves survival whereas alphaSMA-positive depletion worsens it; alphaSMA-specific IL6 loss improves gemcitabine response.", "[11] SHH loss reduces stroma but median survival falls from 6.17 to 3.61 months and gross metastasis rises from 15.3 to 43.4 percent; VEGFR2 blockade selectively rescues the stroma-low setting.", "[12] Approximately 80 percent myofibroblast depletion accelerates aggressive disease and shortens survival despite lower tumor weight; antiCTLA4 increases median survival to 65 versus control 47 days.", "[13] Hedgehog inhibition accelerates pancreatic disease whereas pathway activation expands stroma and reduces epithelial proliferation.", "[14] AlphaSMA-specific Col1 deletion reduces fibrillar collagen/stiffness and accelerates PDAC; CXCR2/CCR2 blockade restores survival toward control.", "[15] SHH overexpression promotes growth and Smo inhibition impairs it while shifting myCAF/iCAF and immune composition.", "[16] FAP-cell and CXCL12 contrasts identify immune exclusion; AMD3100 plus antiPDL1 rapidly removes tumor cells in a defined pancreatic model.", "[17] TGFbeta-rich stroma associates with immune exclusion; combined TGFbeta/PDL1 blockade restores penetration and regression in mouse tumors.", "[18] TGFbeta blockade prevents metastasis and enables checkpoint control of established lesions in low-mutational-burden driver-mutant CRC.", "[19] CSF1R inhibition regresses glioma and prolongs survival through macrophage-state alteration.", "[20] Continued CSF1R blockade produces rebound in 56 percent; rebound cells regain sensitivity in naive hosts, and IGF1R plus CSF1R inhibition extends recurrent-tumor median survival from 13 to 63 days.", "[22] CSF1 deficiency reduces macrophages, angiogenic switching and total pancreatic neuroendocrine tumor burden.", "[23] Macrophage recruitment promotes an angiogenic switch; blocked infiltration delays progression and local restoration restores vascular effects.", "[24] ADAM12-marked slow mesenchymal cells acquire perivascular tumor-supporting states; depletion improves vascular/immune organization and reduces growth.", "[25] Lymphocyte/IFNgamma competence suppresses tumor development and selects tumor immunogenicity.", "[26] Adaptive immune disruption releases occult carcinogen-induced tumors from prolonged equilibrium.", "[27] Immune selection favors preexisting antigen-negative sarcoma clones with defined mutant antigen recognition.", "[28] Type I IFN dependence in host hematopoietic cells differs from IFNgamma tumor-target effects during tumor control.", "[31] VEGFR1-positive progenitor perturbation and reconstitution alter premetastatic niche formation and metastasis in defined models.", "[33] Stable endothelium/TSP1 sustains dormancy whereas sprouting niches and TGFbeta/periostin promote outgrowth.", "[34] Tumor-derived tenascinC supports early metastatic colonization before host stromal supply becomes sufficient.", "[35] Restoring p53 regresses established lymphomas and sarcomas through different apoptosis/senescence responses.", "[36] p53-dependent TSP1 induction contributes to regression after MYC inactivation.", "[37] p16/Rb/p53 senescence machinery influences durable regression after MYC withdrawal.", "[39] Turning off oncogenic KRAS regresses MRI-confirmed invasive tumors within two weeks; selected mice remain tumor-free 23 weeks after withdrawal.", "[40] MYC-off apoptosis/arrest occurs across host immune states, but CD4 loss increases recurrence; CD4 transfer restores durable control and TSP-deficient effectors fail.", "[41] MYC regulates CD47/PDL1 and enforced ligand expression impairs immune remodeling after MYC suppression.", "[42] PanKRAS inhibition suppresses diverse preclinical tumors and remodels tumor/microenvironment state; YAP-associated escape is interrogated.", "[43] GOT2 loss impairs culture but not tested in vivo growth; CAF pyruvate or cytosolic NADH oxidation rescues culture, whereas mitochondrial oxidation does not.", "[44] GOT2 supports PPARdelta-linked immune suppression beyond its proliferative metabolic role.", "[45] Adding bevacizumab to IFL in 813 randomized metastatic colorectal patients increases median survival from 15.6 to 20.3 months, HR0.66.", "[46] Ipilimumab improves median survival versus gp100 from 6.4 to 10.1 months in the defined advanced melanoma trial.", "[47] In 272 previously treated squamous NSCLC patients, nivolumab increases median survival from 6.0 to 9.2 months versus docetaxel, HR0.59.", "[48] In 305 PDL1-high NSCLC patients, pembrolizumab improves PFS from 6.0 to 10.3 months, HR0.50, versus chemotherapy.", "[49] CheckMate067 randomizes 945 melanoma patients; combination/nivolumab/ipilimumab median PFS is 11.5/6.9/2.9 months.", "[50] Ten-year CheckMate067 follow-up reports median OS of 71.9/36.9/19.9 months for combination/nivolumab/ipilimumab.", "[51] CheckMate914 part A in 816 randomized high-risk resected renal patients finds no significant DFS gain, HR0.92, CI0.71–1.19, p0.53.", "[52] RTOG0825 randomizes 637 of 978 registered glioblastoma patients; bevacizumab yields OS15.7 versus16.1 months and worse selected cognitive/QoL outcomes.", "[53] AVAglio in 921 patients improves PFS10.6 versus6.2 months, HR0.64, with no significant OS benefit, p0.10.", "[54] HALO301 has 494 randomized and 492 analysis patients; hyaluronan targeting yields OS11.2 versus11.5 months, HR1.00, and equal PFS7.1 months despite greater response.", "[55] IMmotion150 phase2 randomizes 305 RCC patients; combination versus sunitinib ITT PFS HR1.00, CI0.69–1.45, with immune/angiogenic signatures.", "[56] PTEN loss alters cytokine/autophagy programs, T-cell access and therapy response; PI3Kbeta intervention improves immune control.", "[57] JAK1/2 alterations in rare high-mutational-burden nonresponders impair interferon-linked immune response.", "[58] Four acquired-resistance cases reveal JAK1/2 lesions in two and B2M loss in one with altered antigen/IFN response.", "[59] JAK or B2M disruption produces checkpoint resistance; TLR9/PD1 or CD4/NK/IL2 routes restore selected responses.", "[60] Short VEGF-pathway inhibition/preconditioning can accelerate metastatic growth while suppressing primary tumors.", "[61] VEGF-targeting reduces primary growth yet increases local invasion/metastasis in selected settings.", "[63] ITGB5-positive CAFs alter stromal stiffness and pancreatic ductal adenocarcinoma progression in experimental models with clinical association.", "[64] Stromal FGF1 maintains tumor MYC under RAF/MEK blockade; adding FAK inhibition enables regression in defined pancreatic models." ], "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": "yes", "supporting_evidence": [ "[1] Carcinoma-associated versus normal fibroblasts promote tumor growth from initiated, nontumorigenic prostate epithelium.", "[2] Growth-factor-modified stroma produces malignant outgrowth in 16/18 grafts from one donor; adding normal fibroblasts prevents abnormal outgrowth.", "[3] CAFs from human breast cancers promote growth through SDF1/CXCL12-associated angiogenic recruitment and epithelial CXCR4 signaling.", "[4] LOX-linked matrix crosslinking promotes integrin signaling and invasion; blocking crosslinking reduces fibrosis, tumor incidence and progression.", "[5] Fibroblast caveolin1 influences matrix remodeling, stiffness and invasion with Rho/p190 signaling contrasts.", "[6] A wound/fibrotic environment promotes squamous carcinogenesis with TGFbeta/LOX/integrin pathway contrasts.", "[7] Tumor gain-of-function p53 educates fibroblasts into a perlecan-rich niche supporting invasion and therapy resistance.", "[9] IL1/LIF/JAKSTAT promotes inflammatory CAFs while TGFbeta suppresses IL1R1 and favors myofibroblastic states.", "[10] FAP-positive CAF depletion improves survival whereas alphaSMA-positive depletion worsens it; alphaSMA-specific IL6 loss improves gemcitabine response.", "[11] SHH loss reduces stroma but median survival falls from 6.17 to 3.61 months and gross metastasis rises from 15.3 to 43.4 percent; VEGFR2 blockade selectively rescues the stroma-low setting.", "[12] Approximately 80 percent myofibroblast depletion accelerates aggressive disease and shortens survival despite lower tumor weight; antiCTLA4 increases median survival to 65 versus control 47 days.", "[13] Hedgehog inhibition accelerates pancreatic disease whereas pathway activation expands stroma and reduces epithelial proliferation.", "[14] AlphaSMA-specific Col1 deletion reduces fibrillar collagen/stiffness and accelerates PDAC; CXCR2/CCR2 blockade restores survival toward control.", "[15] SHH overexpression promotes growth and Smo inhibition impairs it while shifting myCAF/iCAF and immune composition.", "[16] FAP-cell and CXCL12 contrasts identify immune exclusion; AMD3100 plus antiPDL1 rapidly removes tumor cells in a defined pancreatic model.", "[17] TGFbeta-rich stroma associates with immune exclusion; combined TGFbeta/PDL1 blockade restores penetration and regression in mouse tumors.", "[18] TGFbeta blockade prevents metastasis and enables checkpoint control of established lesions in low-mutational-burden driver-mutant CRC.", "[19] CSF1R inhibition regresses glioma and prolongs survival through macrophage-state alteration.", "[20] Continued CSF1R blockade produces rebound in 56 percent; rebound cells regain sensitivity in naive hosts, and IGF1R plus CSF1R inhibition extends recurrent-tumor median survival from 13 to 63 days.", "[22] CSF1 deficiency reduces macrophages, angiogenic switching and total pancreatic neuroendocrine tumor burden.", "[23] Macrophage recruitment promotes an angiogenic switch; blocked infiltration delays progression and local restoration restores vascular effects.", "[24] ADAM12-marked slow mesenchymal cells acquire perivascular tumor-supporting states; depletion improves vascular/immune organization and reduces growth.", "[25] Lymphocyte/IFNgamma competence suppresses tumor development and selects tumor immunogenicity.", "[26] Adaptive immune disruption releases occult carcinogen-induced tumors from prolonged equilibrium.", "[27] Immune selection favors preexisting antigen-negative sarcoma clones with defined mutant antigen recognition.", "[28] Type I IFN dependence in host hematopoietic cells differs from IFNgamma tumor-target effects during tumor control.", "[31] VEGFR1-positive progenitor perturbation and reconstitution alter premetastatic niche formation and metastasis in defined models.", "[33] Stable endothelium/TSP1 sustains dormancy whereas sprouting niches and TGFbeta/periostin promote outgrowth.", "[34] Tumor-derived tenascinC supports early metastatic colonization before host stromal supply becomes sufficient.", "[35] Restoring p53 regresses established lymphomas and sarcomas through different apoptosis/senescence responses.", "[36] p53-dependent TSP1 induction contributes to regression after MYC inactivation.", "[37] p16/Rb/p53 senescence machinery influences durable regression after MYC withdrawal.", "[39] Turning off oncogenic KRAS regresses MRI-confirmed invasive tumors within two weeks; selected mice remain tumor-free 23 weeks after withdrawal.", "[40] MYC-off apoptosis/arrest occurs across host immune states, but CD4 loss increases recurrence; CD4 transfer restores durable control and TSP-deficient effectors fail.", "[41] MYC regulates CD47/PDL1 and enforced ligand expression impairs immune remodeling after MYC suppression.", "[42] PanKRAS inhibition suppresses diverse preclinical tumors and remodels tumor/microenvironment state; YAP-associated escape is interrogated.", "[43] GOT2 loss impairs culture but not tested in vivo growth; CAF pyruvate or cytosolic NADH oxidation rescues culture, whereas mitochondrial oxidation does not.", "[44] GOT2 supports PPARdelta-linked immune suppression beyond its proliferative metabolic role.", "[45] Adding bevacizumab to IFL in 813 randomized metastatic colorectal patients increases median survival from 15.6 to 20.3 months, HR0.66.", "[46] Ipilimumab improves median survival versus gp100 from 6.4 to 10.1 months in the defined advanced melanoma trial.", "[47] In 272 previously treated squamous NSCLC patients, nivolumab increases median survival from 6.0 to 9.2 months versus docetaxel, HR0.59.", "[48] In 305 PDL1-high NSCLC patients, pembrolizumab improves PFS from 6.0 to 10.3 months, HR0.50, versus chemotherapy.", "[49] CheckMate067 randomizes 945 melanoma patients; combination/nivolumab/ipilimumab median PFS is 11.5/6.9/2.9 months.", "[50] Ten-year CheckMate067 follow-up reports median OS of 71.9/36.9/19.9 months for combination/nivolumab/ipilimumab.", "[51] CheckMate914 part A in 816 randomized high-risk resected renal patients finds no significant DFS gain, HR0.92, CI0.71–1.19, p0.53.", "[52] RTOG0825 randomizes 637 of 978 registered glioblastoma patients; bevacizumab yields OS15.7 versus16.1 months and worse selected cognitive/QoL outcomes.", "[53] AVAglio in 921 patients improves PFS10.6 versus6.2 months, HR0.64, with no significant OS benefit, p0.10.", "[54] HALO301 has 494 randomized and 492 analysis patients; hyaluronan targeting yields OS11.2 versus11.5 months, HR1.00, and equal PFS7.1 months despite greater response.", "[55] IMmotion150 phase2 randomizes 305 RCC patients; combination versus sunitinib ITT PFS HR1.00, CI0.69–1.45, with immune/angiogenic signatures.", "[56] PTEN loss alters cytokine/autophagy programs, T-cell access and therapy response; PI3Kbeta intervention improves immune control.", "[57] JAK1/2 alterations in rare high-mutational-burden nonresponders impair interferon-linked immune response.", "[58] Four acquired-resistance cases reveal JAK1/2 lesions in two and B2M loss in one with altered antigen/IFN response.", "[59] JAK or B2M disruption produces checkpoint resistance; TLR9/PD1 or CD4/NK/IL2 routes restore selected responses.", "[60] Short VEGF-pathway inhibition/preconditioning can accelerate metastatic growth while suppressing primary tumors.", "[61] VEGF-targeting reduces primary growth yet increases local invasion/metastasis in selected settings.", "[63] ITGB5-positive CAFs alter stromal stiffness and pancreatic ductal adenocarcinoma progression in experimental models with clinical association.", "[64] Stromal FGF1 maintains tumor MYC under RAF/MEK blockade; adding FAK inhibition enables regression in defined pancreatic models." ], "what_would_cross_it": "" }, { "subclaim_id": "SC1", "threshold": "Θ", "requirement_quoted": "Requires that the mechanism explains most of the claimed cancer behavior with only minor exceptions.", "satisfied": "no", "supporting_evidence": [ "[1] Carcinoma-associated versus normal fibroblasts promote tumor growth from initiated, nontumorigenic prostate epithelium.", "[2] Growth-factor-modified stroma produces malignant outgrowth in 16/18 grafts from one donor; adding normal fibroblasts prevents abnormal outgrowth.", "[3] CAFs from human breast cancers promote growth through SDF1/CXCL12-associated angiogenic recruitment and epithelial CXCR4 signaling.", "[4] LOX-linked matrix crosslinking promotes integrin signaling and invasion; blocking crosslinking reduces fibrosis, tumor incidence and progression.", "[5] Fibroblast caveolin1 influences matrix remodeling, stiffness and invasion with Rho/p190 signaling contrasts.", "[6] A wound/fibrotic environment promotes squamous carcinogenesis with TGFbeta/LOX/integrin pathway contrasts.", "[7] Tumor gain-of-function p53 educates fibroblasts into a perlecan-rich niche supporting invasion and therapy resistance.", "[9] IL1/LIF/JAKSTAT promotes inflammatory CAFs while TGFbeta suppresses IL1R1 and favors myofibroblastic states.", "[10] FAP-positive CAF depletion improves survival whereas alphaSMA-positive depletion worsens it; alphaSMA-specific IL6 loss improves gemcitabine response.", "[11] SHH loss reduces stroma but median survival falls from 6.17 to 3.61 months and gross metastasis rises from 15.3 to 43.4 percent; VEGFR2 blockade selectively rescues the stroma-low setting.", "[12] Approximately 80 percent myofibroblast depletion accelerates aggressive disease and shortens survival despite lower tumor weight; antiCTLA4 increases median survival to 65 versus control 47 days.", "[13] Hedgehog inhibition accelerates pancreatic disease whereas pathway activation expands stroma and reduces epithelial proliferation.", "[14] AlphaSMA-specific Col1 deletion reduces fibrillar collagen/stiffness and accelerates PDAC; CXCR2/CCR2 blockade restores survival toward control.", "[15] SHH overexpression promotes growth and Smo inhibition impairs it while shifting myCAF/iCAF and immune composition.", "[16] FAP-cell and CXCL12 contrasts identify immune exclusion; AMD3100 plus antiPDL1 rapidly removes tumor cells in a defined pancreatic model.", "[17] TGFbeta-rich stroma associates with immune exclusion; combined TGFbeta/PDL1 blockade restores penetration and regression in mouse tumors.", "[18] TGFbeta blockade prevents metastasis and enables checkpoint control of established lesions in low-mutational-burden driver-mutant CRC.", "[19] CSF1R inhibition regresses glioma and prolongs survival through macrophage-state alteration.", "[20] Continued CSF1R blockade produces rebound in 56 percent; rebound cells regain sensitivity in naive hosts, and IGF1R plus CSF1R inhibition extends recurrent-tumor median survival from 13 to 63 days.", "[22] CSF1 deficiency reduces macrophages, angiogenic switching and total pancreatic neuroendocrine tumor burden.", "[23] Macrophage recruitment promotes an angiogenic switch; blocked infiltration delays progression and local restoration restores vascular effects.", "[24] ADAM12-marked slow mesenchymal cells acquire perivascular tumor-supporting states; depletion improves vascular/immune organization and reduces growth.", "[25] Lymphocyte/IFNgamma competence suppresses tumor development and selects tumor immunogenicity.", "[26] Adaptive immune disruption releases occult carcinogen-induced tumors from prolonged equilibrium.", "[27] Immune selection favors preexisting antigen-negative sarcoma clones with defined mutant antigen recognition.", "[28] Type I IFN dependence in host hematopoietic cells differs from IFNgamma tumor-target effects during tumor control.", "[31] VEGFR1-positive progenitor perturbation and reconstitution alter premetastatic niche formation and metastasis in defined models.", "[33] Stable endothelium/TSP1 sustains dormancy whereas sprouting niches and TGFbeta/periostin promote outgrowth.", "[34] Tumor-derived tenascinC supports early metastatic colonization before host stromal supply becomes sufficient.", "[35] Restoring p53 regresses established lymphomas and sarcomas through different apoptosis/senescence responses.", "[36] p53-dependent TSP1 induction contributes to regression after MYC inactivation.", "[37] p16/Rb/p53 senescence machinery influences durable regression after MYC withdrawal.", "[39] Turning off oncogenic KRAS regresses MRI-confirmed invasive tumors within two weeks; selected mice remain tumor-free 23 weeks after withdrawal.", "[40] MYC-off apoptosis/arrest occurs across host immune states, but CD4 loss increases recurrence; CD4 transfer restores durable control and TSP-deficient effectors fail.", "[41] MYC regulates CD47/PDL1 and enforced ligand expression impairs immune remodeling after MYC suppression.", "[42] PanKRAS inhibition suppresses diverse preclinical tumors and remodels tumor/microenvironment state; YAP-associated escape is interrogated.", "[43] GOT2 loss impairs culture but not tested in vivo growth; CAF pyruvate or cytosolic NADH oxidation rescues culture, whereas mitochondrial oxidation does not.", "[44] GOT2 supports PPARdelta-linked immune suppression beyond its proliferative metabolic role.", "[45] Adding bevacizumab to IFL in 813 randomized metastatic colorectal patients increases median survival from 15.6 to 20.3 months, HR0.66.", "[46] Ipilimumab improves median survival versus gp100 from 6.4 to 10.1 months in the defined advanced melanoma trial.", "[47] In 272 previously treated squamous NSCLC patients, nivolumab increases median survival from 6.0 to 9.2 months versus docetaxel, HR0.59.", "[48] In 305 PDL1-high NSCLC patients, pembrolizumab improves PFS from 6.0 to 10.3 months, HR0.50, versus chemotherapy.", "[49] CheckMate067 randomizes 945 melanoma patients; combination/nivolumab/ipilimumab median PFS is 11.5/6.9/2.9 months.", "[50] Ten-year CheckMate067 follow-up reports median OS of 71.9/36.9/19.9 months for combination/nivolumab/ipilimumab.", "[51] CheckMate914 part A in 816 randomized high-risk resected renal patients finds no significant DFS gain, HR0.92, CI0.71–1.19, p0.53.", "[52] RTOG0825 randomizes 637 of 978 registered glioblastoma patients; bevacizumab yields OS15.7 versus16.1 months and worse selected cognitive/QoL outcomes.", "[53] AVAglio in 921 patients improves PFS10.6 versus6.2 months, HR0.64, with no significant OS benefit, p0.10.", "[54] HALO301 has 494 randomized and 492 analysis patients; hyaluronan targeting yields OS11.2 versus11.5 months, HR1.00, and equal PFS7.1 months despite greater response.", "[55] IMmotion150 phase2 randomizes 305 RCC patients; combination versus sunitinib ITT PFS HR1.00, CI0.69–1.45, with immune/angiogenic signatures.", "[56] PTEN loss alters cytokine/autophagy programs, T-cell access and therapy response; PI3Kbeta intervention improves immune control.", "[57] JAK1/2 alterations in rare high-mutational-burden nonresponders impair interferon-linked immune response.", "[58] Four acquired-resistance cases reveal JAK1/2 lesions in two and B2M loss in one with altered antigen/IFN response.", "[59] JAK or B2M disruption produces checkpoint resistance; TLR9/PD1 or CD4/NK/IL2 routes restore selected responses.", "[60] Short VEGF-pathway inhibition/preconditioning can accelerate metastatic growth while suppressing primary tumors.", "[61] VEGF-targeting reduces primary growth yet increases local invasion/metastasis in selected settings.", "[63] ITGB5-positive CAFs alter stromal stiffness and pancreatic ductal adenocarcinoma progression in experimental models with clinical association.", "[64] Stromal FGF1 maintains tumor MYC under RAF/MEK blockade; adding FAK inhibition enables regression in defined pancreatic models." ], "what_would_cross_it": "A prespecified causal test matching this subclaim, with mechanistic engagement, meaningful phenotype change and an appropriate negative control." }, { "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": "no", "supporting_evidence": [ "[1] Carcinoma-associated versus normal fibroblasts promote tumor growth from initiated, nontumorigenic prostate epithelium.", "[2] Growth-factor-modified stroma produces malignant outgrowth in 16/18 grafts from one donor; adding normal fibroblasts prevents abnormal outgrowth.", "[4] LOX-linked matrix crosslinking promotes integrin signaling and invasion; blocking crosslinking reduces fibrosis, tumor incidence and progression.", "[6] A wound/fibrotic environment promotes squamous carcinogenesis with TGFbeta/LOX/integrin pathway contrasts.", "[7] Tumor gain-of-function p53 educates fibroblasts into a perlecan-rich niche supporting invasion and therapy resistance.", "[10] FAP-positive CAF depletion improves survival whereas alphaSMA-positive depletion worsens it; alphaSMA-specific IL6 loss improves gemcitabine response.", "[11] SHH loss reduces stroma but median survival falls from 6.17 to 3.61 months and gross metastasis rises from 15.3 to 43.4 percent; VEGFR2 blockade selectively rescues the stroma-low setting.", "[12] Approximately 80 percent myofibroblast depletion accelerates aggressive disease and shortens survival despite lower tumor weight; antiCTLA4 increases median survival to 65 versus control 47 days.", "[13] Hedgehog inhibition accelerates pancreatic disease whereas pathway activation expands stroma and reduces epithelial proliferation.", "[14] AlphaSMA-specific Col1 deletion reduces fibrillar collagen/stiffness and accelerates PDAC; CXCR2/CCR2 blockade restores survival toward control.", "[15] SHH overexpression promotes growth and Smo inhibition impairs it while shifting myCAF/iCAF and immune composition.", "[16] FAP-cell and CXCL12 contrasts identify immune exclusion; AMD3100 plus antiPDL1 rapidly removes tumor cells in a defined pancreatic model.", "[17] TGFbeta-rich stroma associates with immune exclusion; combined TGFbeta/PDL1 blockade restores penetration and regression in mouse tumors.", "[18] TGFbeta blockade prevents metastasis and enables checkpoint control of established lesions in low-mutational-burden driver-mutant CRC.", "[20] Continued CSF1R blockade produces rebound in 56 percent; rebound cells regain sensitivity in naive hosts, and IGF1R plus CSF1R inhibition extends recurrent-tumor median survival from 13 to 63 days.", "[25] Lymphocyte/IFNgamma competence suppresses tumor development and selects tumor immunogenicity.", "[26] Adaptive immune disruption releases occult carcinogen-induced tumors from prolonged equilibrium.", "[27] Immune selection favors preexisting antigen-negative sarcoma clones with defined mutant antigen recognition.", "[33] Stable endothelium/TSP1 sustains dormancy whereas sprouting niches and TGFbeta/periostin promote outgrowth.", "[35] Restoring p53 regresses established lymphomas and sarcomas through different apoptosis/senescence responses.", "[36] p53-dependent TSP1 induction contributes to regression after MYC inactivation.", "[37] p16/Rb/p53 senescence machinery influences durable regression after MYC withdrawal.", "[38] MYC suppression regresses genetically complex lymphomas, with recurrent tumors acquiring replacement alterations.", "[39] Turning off oncogenic KRAS regresses MRI-confirmed invasive tumors within two weeks; selected mice remain tumor-free 23 weeks after withdrawal.", "[40] MYC-off apoptosis/arrest occurs across host immune states, but CD4 loss increases recurrence; CD4 transfer restores durable control and TSP-deficient effectors fail.", "[41] MYC regulates CD47/PDL1 and enforced ligand expression impairs immune remodeling after MYC suppression.", "[42] PanKRAS inhibition suppresses diverse preclinical tumors and remodels tumor/microenvironment state; YAP-associated escape is interrogated.", "[43] GOT2 loss impairs culture but not tested in vivo growth; CAF pyruvate or cytosolic NADH oxidation rescues culture, whereas mitochondrial oxidation does not.", "[44] GOT2 supports PPARdelta-linked immune suppression beyond its proliferative metabolic role.", "[56] PTEN loss alters cytokine/autophagy programs, T-cell access and therapy response; PI3Kbeta intervention improves immune control.", "[57] JAK1/2 alterations in rare high-mutational-burden nonresponders impair interferon-linked immune response.", "[58] Four acquired-resistance cases reveal JAK1/2 lesions in two and B2M loss in one with altered antigen/IFN response.", "[59] JAK or B2M disruption produces checkpoint resistance; TLR9/PD1 or CD4/NK/IL2 routes restore selected responses.", "[60] Short VEGF-pathway inhibition/preconditioning can accelerate metastatic growth while suppressing primary tumors.", "[61] VEGF-targeting reduces primary growth yet increases local invasion/metastasis in selected settings.", "[64] Stromal FGF1 maintains tumor MYC under RAF/MEK blockade; adding FAK inhibition enables regression in defined pancreatic models." ], "what_would_cross_it": "A prespecified causal test matching this subclaim, with mechanistic engagement, meaningful phenotype change and an appropriate negative control." } ], "generalization_check": { "generalization_tested": "yes", "context_boundary_mapped": "yes", "internal_negative_controls": [ "Kuperwasser: nine of ten donors remain nonmalignant, and another region of the responding donor fails to reproduce malignant outgrowth; normal fibroblast addition changes outcome.", "Collagen: Fsp1-directed deletion does not reduce bulk collagen or survival like alphaSMA deletion; baseline vascular integrity is retained and receptor blockade bypasses the phenotype.", "CAF IL6: untreated conditional/global IL6 loss does not improve progression/survival, while gemcitabine response does; allocation unrandomized, histology blinded.", "GOT2: cytosolic but not mitochondrial NADH oxidation rescues culture; functional mitochondrial positive control and endpoint-confirmed MCT1 loss fail to restore in vivo dependence.", "MYC: comparable transgene suppression and initial arrest/apoptosis across immune hosts, but different minimal residual disease/recurrence; CD4 transfer restores durable control.", "CSF1R: target remains inhibited during recurrence, tumor cells lack direct drug sensitivity, and receptor-targeted tumor knockdown tests the adaptive pathway." ], "note": "Initiation, established growth, dormancy, metastasis and treatment-induced resistance are distinct. CAF subsets, collagen source, immune effectors, tumor driver, assay context and intervention timing determine sign. Culture rescue does not identify the unique in vivo mediator. Checkpoint benefit does not prove extrinsic dominance, and driver withdrawal does not prove intrinsic dominance independent of immunity." }, "falsification_patterns_met": [ { "pattern": "Removing nominally promoting stroma worsens the disease endpoint", "evidence": "AlphaSMA/collagen depletion shortens survival and immune bypass rescues, PMID24856586,33667385.", "downgrade_applied": false }, { "pattern": "Tumor-cell driver remains actionable despite a host contribution", "evidence": "Conditional KRAS withdrawal and MYC/immune factorial contrasts, PMID22232209,21035406.", "downgrade_applied": false }, { "pattern": "A proposed in vitro environmental rescue does not uniquely explain in vivo independence", "evidence": "Confirmed MCT1 disruption fails to resensitize GOT2-deficient tumors, PMID35815941.", "downgrade_applied": false } ], "pitfalls_flagged": [ { "pitfall": "Influence substituted for primacy", "where": "Checkpoint/vascular survival benefit is a causal contribution, not comparative dominance." }, { "pitfall": "SHH ligand deletion called stromal-only", "where": "Rhim deletes SHH in pancreatic epithelial lineage; tumor-host signaling is altered jointly." }, { "pitfall": "All fibroblasts treated as one directional compartment", "where": "FAP and alphaSMA depletion have opposite effects." }, { "pitfall": "Reduced tumor weight equated with better survival", "where": "AlphaSMA depletion reduces weight yet increases aggressive disease/embolism mortality." }, { "pitfall": "One long-term trial report counted as independent replication", "where": "CheckMate067 2015 and ten-year report share NCT01844505." }, { "pitfall": "Provider failure to retrieve an original equated with original unavailability", "where": "Consensus misses GOT2, Quail, KRAS and MYC papers that were independently retrieved and examined." }, { "pitfall": "Expression of concern ignored", "where": "Hoshino2015 remains historical but carries no positive causal burden after the August2026 notice." } ], "causal_tally_audit": { "tally_claimed_by_document": 58, "tally_after_audit": 58, "items_rejected": [ "Null and negative contrasts are discriminators, not positive threshold crossings. Reports and replications are not independent causal lines.", "Shared cohorts, experimental platforms, transgenic lineages and repeated outcomes do not constitute fully independent causal lines." ] }, "steelman": { "case_one_rung_higher": "Steelman Δ for broad primacy: naive-host retransplantation resensitizes recurrent glioma and normal fibroblast restoration changes breast outgrowth despite ostensibly similar epithelial cells. These are unusually strong conditional extrinsic contrasts. They do not establish broad endogenous driver-independent maintenance, and transplantation/state reset plus occult donor clones constrain the generalization.", "case_one_rung_lower": "Steelman Β: most human spatial/prognostic associations cannot determine dominance. Γ remains justified by mechanistic rescue and host-changing contrasts; the broader evidence also clearly establishes Η influence, so neither association-only TME nor universally reactive stroma is defensible.", "which_rejected": "Retain Γ for general dominance, Η for compartment-specific causal influence and explicit narrower conditional successes. No additional letter downgrade is imposed for contradictory direction; those results delimit the claim.", "blocking_cap_threshold_or_missing_experiment": "Missing experiment: In several endogenous genotype-defined tumors at matched stages, preregister a factorial intrinsic-driver withdrawal and lineage-specific host perturbation, restoring each separately; track clones and host state through treatment-free relapse and orthogonal immune/metabolic bypass." }, "final_score": { "hsef_level": "Γ", "hsef_descriptor": "Mechanistically plausible, partial system support", "confidence": "Moderate", "confidence_rationale": "64 primary reports with 9 selected partial-body examinations; density, heterogeneous controls and methodological heterogeneity set the confidence, not correctness and not the reviewer's access depth. Re-tested against the High band text, which requires extensive independent replication across labs, models and assay modalities: the band holds at Moderate.", "rests_on_non_peer_reviewed_work": false, "rationale": "Preregistered primary-subclaim SC2 returns Γ. Weakest-link and scope-matched sensitivities also return Γ; SC1 influence reaches Η independently. A narrow macrophage-dependent acquired-resistance state can cross Ε contribution/conditional dominance, but it does not replace the registered broad maintenance/progression claim." }, "role_of_mechanism": { "classification": "reinforcing / stabilizing factor", "derivation_step_matched": 5, "derivation": "Canonical step 5 describes the broad nominal TME mechanism: it changes maintenance/progression and stabilizes selected tumor or escape states without a demonstrated general dominant initiating hierarchy. Defined immune/matrix states also restrain tumors, and scoped resistance can be rate-limiting; the single broad role does not overwrite those directions.", "tournament_used_as_tiebreaker": false, "note": "Derived from causal direction, not tournament rank." }, "extended_scoring_MSD": { "momentum": { "value": "Mechanistic only", "artifact": "2024 innate bypass, 2025 panKRAS and CAF targeting and 2026 spatial state work test specific mechanisms, but none of them addresses the SC2 boundary check, which requires a genotype- and stage-matched factorial comparison of intrinsic-driver withdrawal against lineage-specific host perturbation. No currently recruiting trial or expected pending result is asserted.", "justification": "2024 innate bypass, 2025 panKRAS and CAF targeting and 2026 spatial state work test specific mechanisms, but none of them addresses the SC2 boundary check, which requires a genotype- and stage-matched factorial comparison of intrinsic-driver withdrawal against lineage-specific host perturbation. No currently recruiting trial or expected pending result is asserted." }, "stability": { "value": "Stable", "trigger": "No named pending result is asserted to be likely to move the registered score imminently.", "justification": "No named pending result is asserted to be likely to move the registered score imminently." }, "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": "The two framings carry different implied levels, so no single implied level and no arithmetic gap can be stated. Review and press framing of the microenvironment as the controlling layer of malignant behavior implies a level well above the assessed Γ for dominance, while the endogenous-genetics and randomized-trial literature supports causal influence (Η for SC1) without a dominance comparison. No manufactured field consensus is asserted." }, "calibration_note": "M/S/D never modify HSEF level or confidence." }, "change_record": { "applies": false, "prior_level": "Ranking verdict and index guidance SC1Η/SC2 often belowΔ were visible; freshly adjudicated, not blinded.", "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 several endogenous genotype-defined tumors at matched stages, preregister a factorial intrinsic-driver withdrawal and lineage-specific host perturbation, restoring each separately; track clones and host state through treatment-free relapse and orthogonal immune/metabolic bypass.", "readout": "Engagement in tumor and host, absolute tumor burden, metastasis, survival, residual clones and recurrence after restoration", "critical_control": "Equal initial burden, littermate/lineage controls, tumor-only versus host-only editing, depletion efficiency, pharmacokinetics, injury/toxicity and clone-matched reimplantation controls", "supporting_result": "Host perturbation repeatedly controls maintenance despite retained intrinsic drivers, with host restoration restoring growth and no driver-only dependency across the registered contexts", "falsifying_result": "Driver withdrawal remains necessary, host effect is conditional on driver/immune state, or sign reverses across prespecified compartments" } ], "knowledge_gaps": [ { "name": "Gap 1", "statement": "Run genotype/stage-matched factorial host and tumor-driver perturbations rather than ranking layers from separate positive experiments.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 2", "statement": "Separate immediate arrest from durable eradication, residual clone selection and treatment-free relapse.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 3", "statement": "Resolve why CAF/SHH effects reverse with subset, stage and intervention schedule using independently replicated protocols.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 4", "statement": "Test immune/metabolite bypass after endpoint-confirmed transport disruption; CAF pyruvate culture rescue is not the unique in vivo explanation.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 5", "statement": "Exclude occult premalignant donor clones in normal-tissue humanization with multi-region single-cell genotype/lineage tracking.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 6", "statement": "Distinguish restored host mechanism from bypass rescue, and retain embolic/toxicity mechanisms in survival analysis.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 7", "statement": "Validate spatial/biomarker predictors prospectively with intervention and absolute compartment measurements.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 8", "statement": "Count cohorts/platforms rather than repeated reports as independent evidence and disclose reused expression datasets.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 9", "statement": "Finish unavailable original bodies/supplements and correction contents; audit questioned raw images before any public figure reuse.", "relevance": "Limits mechanism identification or scope." } ], "review_metadata": { "review_date": "2026-10-08", "reviewer": "Codex", "evidence_base_note": "64 primary reports; literature cutoff 2026-10-08; source examination UTC date 2026-10-08; bounded critical review, not exhaustive systematic review.", "literature_tools_available": true, "literature_tools_note": "Life Sciences Literature PubMed/Entrez; attempted Europe PMC XML and successful public NCBI PMC direct HTTPS access are separately logged. Signed-in Consensus browser discovery and targeted indexed full-text checks are reconciled with original sections; failed matches and source substitutions remain explicit. Zero Consensus API calls. SciSpace discovery was also used; matched primary leads were resolved to original records before counting. See scispace-leads.json.", "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": "Endogenous tumor/host genetics, oncogene withdrawal, clonal immune selection and independent survival interventions are live upper-ladder routes and carry SC1 to Η. They do not establish the relative dominance counterfactual for SC2; no RCT-only barrier is imposed. Θ would require most registered behaviors explained with minor exceptions, and Ω necessity/sufficiency across context." }, { "kind": "natural_experiment", "available": false, "why_not_sufficient": "Endogenous tumor/host genetics, oncogene withdrawal, clonal immune selection and independent survival interventions are live upper-ladder routes and carry SC1 to Η. They do not establish the relative dominance counterfactual for SC2; no RCT-only barrier is imposed. Θ would require most registered behaviors explained with minor exceptions, and Ω necessity/sufficiency across context." }, { "kind": "dose_response_across_populations", "available": false, "why_not_sufficient": "Endogenous tumor/host genetics, oncogene withdrawal, clonal immune selection and independent survival interventions are live upper-ladder routes and carry SC1 to Η. They do not establish the relative dominance counterfactual for SC2; no RCT-only barrier is imposed. Θ would require most registered behaviors explained with minor exceptions, and Ω necessity/sufficiency across context." }, { "kind": "withdrawal_rechallenge", "available": false, "why_not_sufficient": "Endogenous tumor/host genetics, oncogene withdrawal, clonal immune selection and independent survival interventions are live upper-ladder routes and carry SC1 to Η. They do not establish the relative dominance counterfactual for SC2; no RCT-only barrier is imposed. Θ would require most registered behaviors explained with minor exceptions, and Ω necessity/sufficiency across context." }, { "kind": "therapeutic_perturbation_hard_endpoint", "available": false, "why_not_sufficient": "Endogenous tumor/host genetics, oncogene withdrawal, clonal immune selection and independent survival interventions are live upper-ladder routes and carry SC1 to Η. They do not establish the relative dominance counterfactual for SC2; no RCT-only barrier is imposed. Θ would require most registered behaviors explained with minor exceptions, and Ω necessity/sufficiency across context." } ], "convergence_present": true, "cap_reapplied_to_convergent_set": false }, "provenance_header": { "sources_total": 64, "claims_total": 67, "claims_verified": 67, "claims_unverified": 0, "claims_contradicted": 0, "tier_a_sources": 64, "generated_by": "Codex; HSEF v5.3", "gate_passed": true }, "claims": [ { "id": "C1", "text": "Carcinoma-associated versus normal fibroblasts promote tumor growth from initiated, nontumorigenic prostate epithelium. Initiated epithelium and xenograft context; not conversion of genetically verified uninitiated cells or general extrinsic dominance.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 1 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C2", "text": "Growth-factor-modified stroma produces malignant outgrowth in 16/18 grafts from one donor; adding normal fibroblasts prevents abnormal outgrowth. Nine of ten donors remain nonmalignant and a different region of the responding breast fails to reproduce malignancy; DNA identity is not exclusion of occult premalignant clones.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 2 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:Publisher HTML paragraphs:paragraph16, 0:Publisher HTML paragraphs:paragraph17, 0:Publisher HTML paragraphs:paragraph39, 0:Publisher HTML paragraphs:paragraph40, 0:Publisher HTML paragraphs:paragraph42, 0:Publisher HTML paragraphs:paragraph43, 0:Publisher HTML paragraphs:paragraph44, 0:Publisher HTML paragraphs:paragraph45, 0:Publisher HTML paragraphs:paragraph46, 0:Publisher HTML paragraphs:paragraph47, 0:Publisher HTML paragraphs:paragraph48, 0:Publisher HTML paragraphs:paragraph53. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C3", "text": "CAFs from human breast cancers promote growth through SDF1/CXCL12-associated angiogenic recruitment and epithelial CXCR4 signaling. Coimplantation with established cancer cells and coupled angiogenesis/proliferation do not establish endogenous universal dominance.", "carries_number": true, "load_bearing_for": [ "SC1" ], "source_ns": [ 3 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C4", "text": "LOX-linked matrix crosslinking promotes integrin signaling and invasion; blocking crosslinking reduces fibrosis, tumor incidence and progression. Oncogene-initiated context; changing mechanics/signaling together is not proof that the matrix overrides all tumor genotypes.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 4 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C5", "text": "Fibroblast caveolin1 influences matrix remodeling, stiffness and invasion with Rho/p190 signaling contrasts. Global host knockout/development and human prognosis association constrain compartment specificity and primacy.", "carries_number": true, "load_bearing_for": [ "SC1" ], "source_ns": [ 5 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C6", "text": "A wound/fibrotic environment promotes squamous carcinogenesis with TGFbeta/LOX/integrin pathway contrasts. Chemical initiation and chronic injury accompany matrix changes; mutation-independent wording does not prove identical normal epithelial genomes/clones.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 6 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C7", "text": "Tumor gain-of-function p53 educates fibroblasts into a perlecan-rich niche supporting invasion and therapy resistance. Tumor genotype organizes the host phenotype; dominance of one CAF state over another is not dominance of host over tumor drivers.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 7 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C8", "text": "Spatially distinct inflammatory and myofibroblastic CAF states emerge in pancreatic models and tissue. Phenotype/state mapping alone is not a survival perturbation or causal hierarchy.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 8 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C9", "text": "IL1/LIF/JAKSTAT promotes inflammatory CAFs while TGFbeta suppresses IL1R1 and favors myofibroblastic states. Tumor ligand output and CAF plasticity are coupled; state selection is not broad malignant maintenance primacy.", "carries_number": true, "load_bearing_for": [ "SC1" ], "source_ns": [ 9 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C10", "text": "FAP-positive CAF depletion improves survival whereas alphaSMA-positive depletion worsens it; alphaSMA-specific IL6 loss improves gemcitabine response. Baseline IL6 deletion leaves progression/survival similar; global IL6 knockout, not solely conditional alphaSMA deletion, supports the tested triple therapy. No allocation randomization, histology blinded; reused alphaSMA data are not independent replication.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 10 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:Publisher HTML paragraphs:paragraph24, 0:Publisher HTML paragraphs:paragraph25, 0:Publisher HTML paragraphs:paragraph28, 0:Publisher HTML paragraphs:paragraph35, 0:Publisher HTML paragraphs:paragraph36, 0:Publisher HTML paragraphs:paragraph39, 0:Publisher HTML paragraphs:paragraph40, 0:Publisher HTML paragraphs:paragraph41, 0:Publisher HTML paragraphs:paragraph42, 0:Publisher HTML paragraphs:paragraph43, 0:Publisher HTML paragraphs:paragraph44, 0:Publisher HTML paragraphs:paragraph56, 0:Publisher HTML paragraphs:paragraph67, 0:Publisher HTML paragraphs:paragraph80, 0:Publisher HTML paragraphs:paragraph38, 0:Publisher HTML paragraphs:paragraph45, 0:Publisher HTML paragraphs:paragraph46, 0:Publisher HTML paragraphs:paragraph50, 0:Publisher HTML paragraphs:paragraph57, 0:Publisher HTML paragraphs:paragraph47, 0:Publisher HTML paragraphs:paragraph48, 0:Publisher HTML paragraphs:paragraph49. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C11", "text": "SHH loss reduces stroma but median survival falls from 6.17 to 3.61 months and gross metastasis rises from 15.3 to 43.4 percent; VEGFR2 blockade selectively rescues the stroma-low setting. SHH deletion is epithelial, not stromal-only; chronic versus acute blockade can have different signs. A suppressive stromal contribution does not prove opposite universal genetic dominance.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 11 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:RESULTS:paragraph0, 1:RESULTS:paragraph1, 1:RESULTS:paragraph2, 1:RESULTS:paragraph4, 1:RESULTS:paragraph6, 1:RESULTS:paragraph7, 1:RESULTS:paragraph11, 1:RESULTS:paragraph13. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C12", "text": "Approximately 80 percent myofibroblast depletion accelerates aggressive disease and shortens survival despite lower tumor weight; antiCTLA4 increases median survival to 65 versus control 47 days. Pulmonary emboli contribute to mortality; sphere/marker enrichment is not CSC proof. Rescue bypasses rather than restores depleted fibroblasts; linked erratum contents unexamined.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 12 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph0, 1:Results:paragraph1, 1:Results:paragraph5, 1:Results:paragraph6, 1:Results:paragraph8. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C13", "text": "Hedgehog inhibition accelerates pancreatic disease whereas pathway activation expands stroma and reduces epithelial proliferation. Stage, genotype and protocol restrict sign; all CAFs and all Hh contexts cannot be called tumor suppressive.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 13 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C14", "text": "AlphaSMA-specific Col1 deletion reduces fibrillar collagen/stiffness and accelerates PDAC; CXCR2/CCR2 blockade restores survival toward control. Fsp1-directed deletion does not similarly reduce total collagen or survival; immune bypass does not restore matrix. Shows compartment-specific restraint rather than generic collagen protection.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 14 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:RESULTS:paragraph0, 1:RESULTS:paragraph1, 1:RESULTS:paragraph6, 1:RESULTS:paragraph7, 1:RESULTS:paragraph8, 1:RESULTS:paragraph11, 1:RESULTS:paragraph20. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C15", "text": "SHH overexpression promotes growth and Smo inhibition impairs it while shifting myCAF/iCAF and immune composition. Contrasts earlier restraining-Hh settings; different stage/protocols prevent one universal directional story.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 15 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C16", "text": "FAP-cell and CXCL12 contrasts identify immune exclusion; AMD3100 plus antiPDL1 rapidly removes tumor cells in a defined pancreatic model. Combined immune/niche dependence in a driver-bearing tumor does not establish host primacy over all intrinsic programs.", "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": "2026-10-08", "note": "" }, { "id": "C17", "text": "TGFbeta-rich stroma associates with immune exclusion; combined TGFbeta/PDL1 blockade restores penetration and regression in mouse tumors. Human biomarker associations are not randomized compartment comparisons; combination efficacy cannot isolate a universal dominant layer.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 17 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C18", "text": "TGFbeta blockade prevents metastasis and enables checkpoint control of established lesions in low-mutational-burden driver-mutant CRC. Specific immune-evasion dependence in a defined tumor genotype; does not erase the required epithelial driver program.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 18 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C19", "text": "CSF1R inhibition regresses glioma and prolongs survival through macrophage-state alteration. TAMs are protected from depletion by glioma signals; functional repolarization, not simply fewer macrophages, explains the tested response.", "carries_number": true, "load_bearing_for": [ "SC1" ], "source_ns": [ 19 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C20", "text": "Continued CSF1R blockade produces rebound in 56 percent; rebound cells regain sensitivity in naive hosts, and IGF1R plus CSF1R inhibition extends recurrent-tumor median survival from 13 to 63 days. Passaging/transplantation can reset state; tumor-specific IGF1R knockdown also restores response. Strong scoped environmental resistance control does not establish general malignant primacy.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 20 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:A subset of GBMs develop resistance to CSF-1R inhibition in long-term preclinical trials, 2:Resistance to CSF-1R inhibition is mediated by the microenvironment, 6:Combination of CSF-1R and IGF-1R inhibition improves outcome. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C21", "text": "Nonirradiative lineage tracing distinguishes brain-resident and recruited macrophage origins with different programs in glioma. Ontogeny and epigenetic association do not alone establish growth dependency or primacy.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 21 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C22", "text": "CSF1 deficiency reduces macrophages, angiogenic switching and total pancreatic neuroendocrine tumor burden. Established tumors retain growth with compensating neutrophils; developmental effects and redundant myeloid routes limit universal necessity.", "carries_number": true, "load_bearing_for": [ "SC1" ], "source_ns": [ 22 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C23", "text": "Macrophage recruitment promotes an angiogenic switch; blocked infiltration delays progression and local restoration restores vascular effects. A defined angiogenic stage and transgenic platform, not all epithelial initiation or maintenance.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 23 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C24", "text": "ADAM12-marked slow mesenchymal cells acquire perivascular tumor-supporting states; depletion improves vascular/immune organization and reduces growth. State and lineage restriction, tumor-induced remodeling and different cell populations constrain a unifying stromal hierarchy.", "carries_number": true, "load_bearing_for": [ "SC1" ], "source_ns": [ 24 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C25", "text": "Lymphocyte/IFNgamma competence suppresses tumor development and selects tumor immunogenicity. Host deficiency and carcinogen initiation are broad changes; immune editing is not immunity-only control of every malignant behavior.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 25 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C26", "text": "Adaptive immune disruption releases occult carcinogen-induced tumors from prolonged equilibrium. Transformed cells preexist; immune containment and eventual escape do not specify universal host primacy.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 26 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C27", "text": "Immune selection favors preexisting antigen-negative sarcoma clones with defined mutant antigen recognition. Related immunoediting platform; genotype and immunity interact rather than forming separable universal hierarchies.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 27 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C28", "text": "Type I IFN dependence in host hematopoietic cells differs from IFNgamma tumor-target effects during tumor control. Conditional cell targets, not all immune pathways; linked erratum contents unexamined.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 28 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C29", "text": "Germline epitope repertoire associates with recurrent tumor alterations across 5870 lesions. Computational selection and population associations are not randomized immune perturbation; earlier preprint is the same study.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 29 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C30", "text": "258 regions from 88 lung tumors reveal antigen-presentation loss and neoantigen expression/loss trajectories compatible with immune selection. Observational clonal tracking infers selection but does not experimentally compare intrinsic and host primacy.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 30 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C31", "text": "VEGFR1-positive progenitor perturbation and reconstitution alter premetastatic niche formation and metastasis in defined models. Transplant/conditioned-medium and recruitment context; does not prove all spontaneous metastasis requires this niche.", "carries_number": true, "load_bearing_for": [ "SC1" ], "source_ns": [ 31 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C32", "text": "The original report proposed organotropic exosomal integrins directing uptake and metastatic niche formation. Nature expression of concern published 5 August 2026 identifies potentially overlapping images; excluded from positive load-bearing causal evidence. No raw-image audit or retraction claimed.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 32 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C33", "text": "Stable endothelium/TSP1 sustains dormancy whereas sprouting niches and TGFbeta/periostin promote outgrowth. Defined disseminated-cell contexts; unchanged genome cannot be presumed solely from similar cell lineage, and all malignant maintenance is broader.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 33 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C34", "text": "Tumor-derived tenascinC supports early metastatic colonization before host stromal supply becomes sufficient. The niche effector initially originates from tumor cells; intrinsic/extrinsic boundary is mechanistically coupled.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 34 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C35", "text": "Restoring p53 regresses established lymphomas and sarcomas through different apoptosis/senescence responses. Tumor-type-dependent genetic restoration can remodel host effectors; not proof that every cancer is intrinsically dominant.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 35 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C36", "text": "p53-dependent TSP1 induction contributes to regression after MYC inactivation. TSP1 alone does not suppress MYC-on growth; joint oncogene/host mechanism rather than either universal primacy.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 36 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C37", "text": "p16/Rb/p53 senescence machinery influences durable regression after MYC withdrawal. Cell-state and host effects cooperate; restricted transgenic programs do not define all sporadic cancers.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 37 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C38", "text": "MYC suppression regresses genetically complex lymphomas, with recurrent tumors acquiring replacement alterations. Driver substitution after selection and transgene withdrawal differ from uniform endogenous human dependence.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 38 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C39", "text": "Turning off oncogenic KRAS regresses MRI-confirmed invasive tumors within two weeks; selected mice remain tumor-free 23 weeks after withdrawal. Transgenic expression, p53 background and cerulein injury restrict inference; small MRI cohort and simultaneous stromal remodeling do not establish opposite universal genetic primacy.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 39 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:Publisher HTML paragraphs:paragraph71, 0:Publisher HTML paragraphs:paragraph73, 0:Publisher HTML paragraphs:paragraph74, 0:Publisher HTML paragraphs:paragraph75, 0:Publisher HTML paragraphs:paragraph76, 0:Publisher HTML paragraphs:paragraph80, 0:Publisher HTML paragraphs:paragraph83, 0:Publisher HTML paragraphs:paragraph84, 0:Publisher HTML paragraphs:paragraph85. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C40", "text": "MYC-off apoptosis/arrest occurs across host immune states, but CD4 loss increases recurrence; CD4 transfer restores durable control and TSP-deficient effectors fail. Initial and durable responses differ; immune bypass and intrinsic withdrawal jointly determine control. PubMed Comment label accompanies genuine original experiments; linked erratum unexamined.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 40 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph0, 1:Results:paragraph1, 1:Results:paragraph2, 1:Results:paragraph4, 1:Results:paragraph5, 1:Results:paragraph10, 1:Results:paragraph14, 1:Results:paragraph15, 1:Results:paragraph16, 1:Results:paragraph17. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C41", "text": "MYC regulates CD47/PDL1 and enforced ligand expression impairs immune remodeling after MYC suppression. Tumor genotype drives immune output; linked erratum27124464 metadata verified, contents unexamined.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 41 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C42", "text": "PanKRAS inhibition suppresses diverse preclinical tumors and remodels tumor/microenvironment state; YAP-associated escape is interrogated. Drug specificity and feedback matter; preclinical results are not patient efficacy or universal intrinsic dominance.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 42 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C43", "text": "GOT2 loss impairs culture but not tested in vivo growth; CAF pyruvate or cytosolic NADH oxidation rescues culture, whereas mitochondrial oxidation does not. Confirmed MCT1 loss/inhibition fails to resensitize tumors in vivo, so CAF pyruvate is not established as the unique in vivo explanation; residual/alternative redox routes remain.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 43 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph14, 1:Results:paragraph17, 1:Results:paragraph23, 1:Results:paragraph27, 1:Results:paragraph34, 1:Results:paragraph36, 1:Results:paragraph40, 1:Results:paragraph55. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C44", "text": "GOT2 supports PPARdelta-linked immune suppression beyond its proliferative metabolic role. Different tumor/immune conditions and enzyme functions prevent treating context papers as a direct universal contradiction.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 44 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C45", "text": "Adding bevacizumab to IFL in 813 randomized metastatic colorectal patients increases median survival from 15.6 to 20.3 months, HR0.66. Antiangiogenic/additive clinical benefit is not a matched comparison with extinguishing tumor drivers; delivery and vascular functions are coupled.", "carries_number": true, "load_bearing_for": [ "SC1" ], "source_ns": [ 45 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C46", "text": "Ipilimumab improves median survival versus gp100 from 6.4 to 10.1 months in the defined advanced melanoma trial. Selected HLA/treatment population and immune toxicity; survival benefit does not prove broad extrinsic dominance. Linked erratum contents unexamined.", "carries_number": true, "load_bearing_for": [ "SC1" ], "source_ns": [ 46 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C47", "text": "In 272 previously treated squamous NSCLC patients, nivolumab increases median survival from 6.0 to 9.2 months versus docetaxel, HR0.59. Specific disease/treatment comparison; PDL1 nonprediction in this study does not mean genotype or tumor state is irrelevant.", "carries_number": true, "load_bearing_for": [ "SC1" ], "source_ns": [ 47 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C48", "text": "In 305 PDL1-high NSCLC patients, pembrolizumab improves PFS from 6.0 to 10.3 months, HR0.50, versus chemotherapy. Enrollment excludes sensitizing EGFR and ALK alterations and requires PDL1 at least 50 percent; cannot generalize to all genotypes.", "carries_number": true, "load_bearing_for": [ "SC1" ], "source_ns": [ 48 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C49", "text": "CheckMate067 randomizes 945 melanoma patients; combination/nivolumab/ipilimumab median PFS is 11.5/6.9/2.9 months. Initial report emphasizes PFS; later long-term survival is the same trial, not independent replication. Linked erratum31442371 contents unexamined.", "carries_number": true, "load_bearing_for": [ "SC1" ], "source_ns": [ 49 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C50", "text": "Ten-year CheckMate067 follow-up reports median OS of 71.9/36.9/19.9 months for combination/nivolumab/ipilimumab. Same NCT01844505 cohort as the 2015 report; online 2024 and journal issue 2025, not a new independent trial.", "carries_number": true, "load_bearing_for": [ "SC1" ], "source_ns": [ 50 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C51", "text": "CheckMate914 part A in 816 randomized high-risk resected renal patients finds no significant DFS gain, HR0.92, CI0.71–1.19, p0.53. Specific adjuvant regimen and 32 versus 2 percent toxicity discontinuation; null is not proof immunity never controls RCC.", "carries_number": true, "load_bearing_for": [ "SC1" ], "source_ns": [ 51 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C52", "text": "RTOG0825 randomizes 637 of 978 registered glioblastoma patients; bevacizumab yields OS15.7 versus16.1 months and worse selected cognitive/QoL outcomes. PFS10.7 versus7.3 months does not meet preset improvement; vascular imaging/response changes are not survival proof.", "carries_number": true, "load_bearing_for": [ "SC1" ], "source_ns": [ 52 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C53", "text": "AVAglio in 921 patients improves PFS10.6 versus6.2 months, HR0.64, with no significant OS benefit, p0.10. QoL instruments/protocol differ from RTOG0825; do not collapse different QoL findings or infer absent vascular biology.", "carries_number": true, "load_bearing_for": [ "SC1" ], "source_ns": [ 53 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C54", "text": "HALO301 has 494 randomized and 492 analysis patients; hyaluronan targeting yields OS11.2 versus11.5 months, HR1.00, and equal PFS7.1 months despite greater response. Hyaluronan-high selected disease, toxicity and drug regimen; response is not survival and null does not negate all stromal contributions.", "carries_number": true, "load_bearing_for": [ "SC1" ], "source_ns": [ 54 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C55", "text": "IMmotion150 phase2 randomizes 305 RCC patients; combination versus sunitinib ITT PFS HR1.00, CI0.69–1.45, with immune/angiogenic signatures. TMB is not associated with PFS in this study; biomarker signatures do not prove layer primacy. Linked correction30291359 contents unexamined.", "carries_number": true, "load_bearing_for": [ "SC1" ], "source_ns": [ 55 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C56", "text": "PTEN loss alters cytokine/autophagy programs, T-cell access and therapy response; PI3Kbeta intervention improves immune control. Intrinsic genetic and host pathways are causally coupled, not separable universal dominant compartments.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 56 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C57", "text": "JAK1/2 alterations in rare high-mutational-burden nonresponders impair interferon-linked immune response. One of 23 melanoma and one of 16 colorectal patients; rare cases and cell assays do not establish population-wide primacy.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 57 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C58", "text": "Four acquired-resistance cases reveal JAK1/2 lesions in two and B2M loss in one with altered antigen/IFN response. Small selected series; antigen presentation and IFN mechanisms differ and do not cover all immune escape.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 58 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C59", "text": "JAK or B2M disruption produces checkpoint resistance; TLR9/PD1 or CD4/NK/IL2 routes restore selected responses. Genetically imposed immune escape can be bypassed, opposing immutable genetic dominance; engineered models do not establish universal immune primacy.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 59 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C60", "text": "Short VEGF-pathway inhibition/preconditioning can accelerate metastatic growth while suppressing primary tumors. Pretreatment, intravenous/resection context and short schedule cannot be equated with prolonged human therapy effects.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 60 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C61", "text": "VEGF-targeting reduces primary growth yet increases local invasion/metastasis in selected settings. Stage, hypoxia and vessel mechanism can change sign; no claim that all antiangiogenic clinical treatment increases metastasis.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 61 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C62", "text": "Tumor identity and malignant programs associate with spatial immune/stromal neighborhoods in untreated pancreatic ductal adenocarcinoma from 39 patients. Before-cutoff 2026 report; observational spatial association does not identify directional causal dominance.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 62 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C63", "text": "ITGB5-positive CAFs alter stromal stiffness and pancreatic ductal adenocarcinoma progression in experimental models with clinical association. Prognostic/registration statements in the abstract are not independently verified clinical validation; binding/signaling and matrix state vary together.", "carries_number": true, "load_bearing_for": [ "SC1" ], "source_ns": [ 63 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C64", "text": "Stromal FGF1 maintains tumor MYC under RAF/MEK blockade; adding FAK inhibition enables regression in defined pancreatic models. Joint pathway treatment reinforces tumor/host feedback; a 2024 trial statement does not establish current recruitment or clinical efficacy.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 64 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "CSC1", "text": "Η: endogenous compartment-specific loss, immune restoration, relapse/resistance tests and independent clinical survival interventions establish causal TME influence within explicitly defined compartments/settings. They reject the claim that all TME change is reactive; they do not make every stromal factor rate-limiting.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-08", "note": "" }, { "id": "CSC2", "text": "Γ: scoped host-dependent resistance and tissue-humanization models support primacy as a mechanistic possibility. Paired evidence also shows continued intrinsic dependencies and joint immune/oncogene requirements. The registered general dominance claim lacks convergent endogenous factorial comparisons; influence cannot substitute for primacy.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 1, 2, 4, 6, 7, 10, 11, 12, 13, 14, 15, 16, 17, 18, 20, 25, 26, 27, 29, 30, 33, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 56, 57, 58, 59, 60, 61, 62, 64 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-08", "note": "" }, { "id": "CH", "text": "Tumor microenvironments causally change growth, immune escape, dormancy and treatment outcomes, but general dominance over tumor genetics is not established.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 11, 14, 20, 39, 40, 45, 50 ], "verification": "verified", "verified_against": "Bounded synthesis of examined sources; score is adjudication.", "verified_on": "2026-10-08", "note": "" } ], "citation_ledger": [ { "n": 1, "citation": "Olumi AF, Grossfeld GD, Hayward SW et al. Carcinoma-associated fibroblasts direct tumor progression of initiated human prostatic epithelium. Cancer research. 1999.", "tier": "A", "kind": "primary", "pmid": "10519415", "doi": "", "url": "https://pubmed.ncbi.nlm.nih.gov/10519415/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID10519415", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C1", "CSC1", "CSC2" ] }, { "n": 2, "citation": "Kuperwasser C, Chavarria T, Wu M et al. Reconstruction of functionally normal and malignant human breast tissues in mice. Proceedings of the National Academy of Sciences of the United States of America. 2004.", "tier": "A", "kind": "primary", "pmid": "15051869", "doi": "10.1073/pnas.0401064101", "url": "https://pubmed.ncbi.nlm.nih.gov/15051869/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID15051869", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:Publisher HTML paragraphs:paragraph16, 0:Publisher HTML paragraphs:paragraph17, 0:Publisher HTML paragraphs:paragraph39, 0:Publisher HTML paragraphs:paragraph40, 0:Publisher HTML paragraphs:paragraph42, 0:Publisher HTML paragraphs:paragraph43, 0:Publisher HTML paragraphs:paragraph44, 0:Publisher HTML paragraphs:paragraph45, 0:Publisher HTML paragraphs:paragraph46, 0:Publisher HTML paragraphs:paragraph47, 0:Publisher HTML paragraphs:paragraph48, 0:Publisher HTML paragraphs:paragraph53. No complete-paper or supplement audit claimed.", "carries_claims": [ "C2", "CSC1", "CSC2" ] }, { "n": 3, "citation": "Orimo A, Gupta PB, Sgroi DC et al. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell. 2005.", "tier": "A", "kind": "primary", "pmid": "15882617", "doi": "10.1016/j.cell.2005.02.034", "url": "https://pubmed.ncbi.nlm.nih.gov/15882617/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID15882617", "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" ] }, { "n": 4, "citation": "Levental KR, Yu H, Kass L et al. Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell. 2009.", "tier": "A", "kind": "primary", "pmid": "19931152", "doi": "10.1016/j.cell.2009.10.027", "url": "https://pubmed.ncbi.nlm.nih.gov/19931152/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID19931152", "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", "CSC2" ] }, { "n": 5, "citation": "Goetz JG, Minguet S, Navarro-Lérida I et al. Biomechanical remodeling of the microenvironment by stromal caveolin-1 favors tumor invasion and metastasis. Cell. 2011.", "tier": "A", "kind": "primary", "pmid": "21729786", "doi": "10.1016/j.cell.2011.05.040", "url": "https://pubmed.ncbi.nlm.nih.gov/21729786/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID21729786", "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" ] }, { "n": 6, "citation": "Mittapalli VR, Madl J, Löffek S et al. Injury-Driven Stiffening of the Dermis Expedites Skin Carcinoma Progression. Cancer research. 2016.", "tier": "A", "kind": "primary", "pmid": "26676755", "doi": "10.1158/0008-5472.CAN-15-1348", "url": "https://pubmed.ncbi.nlm.nih.gov/26676755/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID26676755", "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", "CSC2" ] }, { "n": 7, "citation": "Vennin C, Mélénec P, Rouet R et al. CAF hierarchy driven by pancreatic cancer cell p53-status creates a pro-metastatic and chemoresistant environment via perlecan. Nature communications. 2019.", "tier": "A", "kind": "primary", "pmid": "31406163", "doi": "10.1038/s41467-019-10968-6", "url": "https://pubmed.ncbi.nlm.nih.gov/31406163/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID31406163", "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", "CSC2" ] }, { "n": 8, "citation": "Öhlund D, Handly-Santana A, Biffi G et al. Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer. The Journal of experimental medicine. 2017.", "tier": "A", "kind": "primary", "pmid": "28232471", "doi": "10.1084/jem.20162024", "url": "https://pubmed.ncbi.nlm.nih.gov/28232471/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID28232471", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C8", "CSC1" ] }, { "n": 9, "citation": "Biffi G, Oni TE, Spielman B et al. IL1-Induced JAK/STAT Signaling Is Antagonized by TGFβ to Shape CAF Heterogeneity in Pancreatic Ductal Adenocarcinoma. Cancer discovery. 2019.", "tier": "A", "kind": "primary", "pmid": "30366930", "doi": "10.1158/2159-8290.CD-18-0710", "url": "https://pubmed.ncbi.nlm.nih.gov/30366930/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID30366930", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C9", "CSC1" ] }, { "n": 10, "citation": "McAndrews KM, Chen Y, Darpolor JK et al. Identification of Functional Heterogeneity of Carcinoma-Associated Fibroblasts with Distinct IL6-Mediated Therapy Resistance in Pancreatic Cancer. Cancer discovery. 2022.", "tier": "A", "kind": "primary", "pmid": "35348629", "doi": "10.1158/2159-8290.CD-20-1484", "url": "https://pubmed.ncbi.nlm.nih.gov/35348629/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID35348629", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:Publisher HTML paragraphs:paragraph24, 0:Publisher HTML paragraphs:paragraph25, 0:Publisher HTML paragraphs:paragraph28, 0:Publisher HTML paragraphs:paragraph35, 0:Publisher HTML paragraphs:paragraph36, 0:Publisher HTML paragraphs:paragraph39, 0:Publisher HTML paragraphs:paragraph40, 0:Publisher HTML paragraphs:paragraph41, 0:Publisher HTML paragraphs:paragraph42, 0:Publisher HTML paragraphs:paragraph43, 0:Publisher HTML paragraphs:paragraph44, 0:Publisher HTML paragraphs:paragraph56, 0:Publisher HTML paragraphs:paragraph67, 0:Publisher HTML paragraphs:paragraph80, 0:Publisher HTML paragraphs:paragraph38, 0:Publisher HTML paragraphs:paragraph45, 0:Publisher HTML paragraphs:paragraph46, 0:Publisher HTML paragraphs:paragraph50, 0:Publisher HTML paragraphs:paragraph57, 0:Publisher HTML paragraphs:paragraph47, 0:Publisher HTML paragraphs:paragraph48, 0:Publisher HTML paragraphs:paragraph49. No complete-paper or supplement audit claimed.", "carries_claims": [ "C10", "CSC1", "CSC2" ] }, { "n": 11, "citation": "Rhim AD, Oberstein PE, Thomas DH et al. Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. Cancer cell. 2014.", "tier": "A", "kind": "primary", "pmid": "24856585", "doi": "10.1016/j.ccr.2014.04.021", "url": "https://pubmed.ncbi.nlm.nih.gov/24856585/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID24856585", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:RESULTS:paragraph0, 1:RESULTS:paragraph1, 1:RESULTS:paragraph2, 1:RESULTS:paragraph4, 1:RESULTS:paragraph6, 1:RESULTS:paragraph7, 1:RESULTS:paragraph11, 1:RESULTS:paragraph13. No complete-paper or supplement audit claimed.", "carries_claims": [ "C11", "CSC1", "CSC2", "CH" ] }, { "n": 12, "citation": "Özdemir BC, Pentcheva-Hoang T, Carstens JL et al. Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer cell. 2014.", "tier": "A", "kind": "primary", "pmid": "24856586", "doi": "10.1016/j.ccr.2014.04.005", "url": "https://pubmed.ncbi.nlm.nih.gov/24856586/", "status_flags": [ "ErratumIn: PMID not supplied" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID24856586", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph0, 1:Results:paragraph1, 1:Results:paragraph5, 1:Results:paragraph6, 1:Results:paragraph8. No complete-paper or supplement audit claimed.", "carries_claims": [ "C12", "CSC1", "CSC2" ] }, { "n": 13, "citation": "Lee JJ, Perera RM, Wang H et al. Stromal response to Hedgehog signaling restrains pancreatic cancer progression. Proceedings of the National Academy of Sciences of the United States of America. 2014.", "tier": "A", "kind": "primary", "pmid": "25024225", "doi": "10.1073/pnas.1411679111", "url": "https://pubmed.ncbi.nlm.nih.gov/25024225/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID25024225", "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", "CSC2" ] }, { "n": 14, "citation": "Chen Y, Kim J, Yang S et al. Type I collagen deletion in αSMA+ myofibroblasts augments immune suppression and accelerates progression of pancreatic cancer. Cancer cell. 2021.", "tier": "A", "kind": "primary", "pmid": "33667385", "doi": "10.1016/j.ccell.2021.02.007", "url": "https://pubmed.ncbi.nlm.nih.gov/33667385/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID33667385", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:RESULTS:paragraph0, 1:RESULTS:paragraph1, 1:RESULTS:paragraph6, 1:RESULTS:paragraph7, 1:RESULTS:paragraph8, 1:RESULTS:paragraph11, 1:RESULTS:paragraph20. No complete-paper or supplement audit claimed.", "carries_claims": [ "C14", "CSC1", "CSC2", "CH" ] }, { "n": 15, "citation": "Steele NG, Biffi G, Kemp SB et al. Inhibition of Hedgehog Signaling Alters Fibroblast Composition in Pancreatic Cancer. Clinical cancer research : an official journal of the American Association for Cancer Research. 2021.", "tier": "A", "kind": "primary", "pmid": "33495315", "doi": "10.1158/1078-0432.CCR-20-3715", "url": "https://pubmed.ncbi.nlm.nih.gov/33495315/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID33495315", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C15", "CSC1", "CSC2" ] }, { "n": 16, "citation": "Feig C, Jones JO, Kraman M et al. Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. 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