Functional hierarchies and relapse-sustaining cell states occur in particular tumours. Permissive transplantation and lineage-resolved state switching challenge a universal rare, fixed and irreplaceable compartment.
This dated addendum adds selected evidence and tests that could resolve the remaining questions. It does not regrade the archived review.
Each question identifies a limit in the checked evidence. A missing search result alone does not establish a gap in the entire field.
Competing explanation: Host permissiveness and sorting may create apparent rarity.
Discriminating test: Pair transplantation with endogenous lineage tracing; vary recipient immune status, matrix and cell viability while fixing sampling and follow-up.
Competing explanation: Apparent escape may reflect incomplete ablation or true state conversion.
Discriminating test: Permanent pre-ablation lineage labels and ablation-efficiency measurement; distinguish residual target cells from converted progeny over long follow-up.
Competing explanation: A relapse-specific state may differ from the primary-tumour initiating population.
Discriminating test: Track residual states after standard therapy or surgery; randomize state-specific targeting and assess relapse, not transplantation alone.
Competing explanation: Off-target killing or niche alteration may produce benefit while other states replenish function.
Discriminating test: Biomarker-stratified human trials with paired biopsies, target depletion, escape-state tracking, hard outcomes and combination controls.
Electronic publication dates are used where recorded, with issue years shown separately. This is a selected chronology, not a claim of scientific priority or independent replication for every entry.
A prospectively isolated compartment serially generated heterogeneous leukemia.
What it cannot establish: Transplantation sufficiency depends on host and assay; endogenous universal necessity is separate.
Marker-selected cells generated and serially propagated heterogeneous tumours.
What it cannot establish: Assay selection and patient context bound the inference.
Changing host/assay conditions revealed frequent tumour-forming capacity, including single-cell transplants.
What it cannot establish: Tumour formation in a recipient does not identify an endogenous fixed hierarchy.
A relatively quiescent population sustained regrowth after chemotherapy; ablation restricted growth.
What it cannot establish: Dependency applies to the tested model and treatment setting.
Lgr5-positive cells self-renewed and generated other adenoma cells.
What it cannot establish: Adenoma lineage behaviour does not generalize automatically to invasive carcinoma.
Differentiated cells reverted and contributed to regrowth after LGR5-positive depletion.
What it cannot establish: Organoid/xenograft plasticity is distinct from patient relapse under therapeutic targeting.
Lgr5-negative cells maintained primary tumours and replenished the Lgr5-positive pool.
What it cannot establish: Primary and metastatic dependencies differed.
Lgr5-negative disseminated cells acquired stem-like capacity during metastatic outgrowth.
What it cannot establish: Establishment and outgrowth are different causal stages.
Residual EMP1-high cells generated recurrence; their ablation prevented relapse.
What it cannot establish: A specific residual state and model do not establish a universal marker-defined apex.
A high-plasticity state contributed to progression and treatment resistance.
What it cannot establish: State targeting and context-specific necessity do not prove irreplaceability across tumours.
ZFP36L2 regulated stress-adaptive dedifferentiation and lineage plasticity.
What it cannot establish: Loss of canonical stem-state entry can permit alternative malignant states.
Case-specific Consensus records assisted gap discovery, chronology and targeted paper questions. Shared template wording about an amyloid-specific Deep follow-up is not evidence of a Deep run for this topic; the dated source records establish the actual use and access limits. Primary identifiers, selected abstract passages, correction notices and available primary-body passages were cross-checked. Generated absence cells, duplicate milestones and unsupported access claims were rejected.
Single-cell figure passage and Methods Summary P25: single cells were mixed with Matrigel and transplanted into permissive hosts; host/assay conditions are explicit.
This focused addendum does not establish 50–70 complete primary Methods/Results examinations per review. Baseline reading receipts and scores retain their original scope.
Selected full-text checks: 1; abstract checks: 10; metadata-only anchors: 0. Complete-paper examinations credited in this update: 0.
New enrichment: HSEF v5.3 causal distinctions. Archived scorecard schema: 5.4; retained as recorded.
Consensus often cited later reviews for original experimental claims. Those citations were not accepted as primary verification.
PMID 9212098 · DOI 10.1038/nm0797-730
Selected abstract passages checked. Primary record and selected abstract passages checked; no complete-paper appraisal credited.
PMID 12629218 · DOI 10.1073/pnas.0530291100
Selected abstract passages checked. Primary record and selected abstract passages checked; no complete-paper appraisal credited.
Linked notices: Correction (identifier unavailable in this record)
Linked notice presence was checked in the primary record; its scientific impact was not verified in this update.
PMID 19052619 · DOI 10.1038/nature07567
Selected full-text passages checked. Single-cell figure passage and Methods Summary P25: single cells were mixed with Matrigel and transplanted into permissive hosts; host/assay conditions are explicit.
PMID 22855427 · DOI 10.1126/science.1224676
Selected abstract passages checked. Primary record and selected abstract passages checked; no complete-paper appraisal credited.
PMID 22854781 · DOI 10.1038/nature11287
Selected abstract passages checked. Primary record and selected abstract passages checked; no complete-paper appraisal credited.
PMID 28358093 · DOI 10.1038/nature21713
Selected abstract passages checked. Primary record and selected abstract passages checked; no complete-paper appraisal credited.
PMID 28355176 · DOI 10.1038/nature22081
Selected abstract passages checked. Primary record and selected abstract passages checked; no complete-paper appraisal credited.
PMID 32169167 · DOI 10.1016/j.stem.2020.02.008
Selected abstract passages checked. Primary record and selected abstract passages checked; no complete-paper appraisal credited.
PMID 36352230 · DOI 10.1038/s41586-022-05402-9
Selected abstract passages checked. Primary record and selected abstract passages checked; no complete-paper appraisal credited.
PMID 41565826 · DOI 10.1038/s41586-025-09985-x
Selected abstract passages checked. Primary record and selected abstract passages checked; no complete-paper appraisal credited.
PMID 42557330 · DOI 10.1038/s41586-026-10890-0
Selected abstract passages checked. Primary record and selected abstract passages checked; no complete-paper appraisal credited.
Read the dated addendum · Video script and storyboard insert · References (RIS) · References (BibTeX)