# Cancer stem cells & phenotypic plasticity

Source: https://onco.cc/pathways/cancer-stem-cells-plasticity/  
OnCo record `cancer-stem-cells-plasticity` (Pathway). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Some cancer cells behave like stem cells: they can regrow the whole tumour, resist treatment, and switch identities. This plasticity explains why tumours come back and why some lung and prostate cancers transform into a different cancer type under therapy.

## Summary

Cancer stem cells (CSCs; first shown in AML by Dick, 1994-97) are functionally defined by tumour-initiating capacity; in solid tumours stemness is usually a reversible state rather than a fixed population. Lineage plasticity under therapy produces neuroendocrine transformation (EGFR-mutant NSCLC to SCLC; prostate adenocarcinoma to NEPC), basal/mesenchymal switching in breast cancer, and dedifferentiation. Drivers: EMT programmes, Wnt/Notch/Hedgehog, epigenetic remodelling (EZH2, SWI/SNF), TP53/RB1 loss. 'Unlocking phenotypic plasticity' is a 2022 hallmark. Therapeutic routes: differentiation therapy (ATRA in APL), EZH2/LSD1 inhibitors, targeting CSC markers (CD44, LGR5), and MRD-directed therapy.

## Fields

- Kind: Pathway
- Last checked: 2026-09-08
- Tags: mechanism
- Analogy: A weed that can turn from leaf to root to seed depending on what you spray on it. Kill the leaves and the roots wait; kill the roots and a seed reawakens.
- Interventions: Differentiation therapy: ATRA/arsenic in APL (curative), menin inhibitors differentiate KMT2A/NPM1 leukaemias; EZH2, LSD1, and BET inhibitors to block plasticity (trials); DLL3-directed tarlatamab for neuroendocrine-transformed tumours; MRD-directed therapy to catch persisters before regrowth

## Notes

- Leading programmes: Dick (Princess Margaret, leukaemia stem cells); Sawyers and Rudin (MSK, lineage plasticity in prostate and lung); Clevers (Hubrecht, organoids and LGR5); Weissman (Stanford).

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Cancer_stem_cell
- Rubin, Bristow, Thienger et al., Impact of lineage plasticity to and from a neuroendocrine phenotype (Molecular Cell 2020): https://doi.org/10.1016/j.molcel.2020.10.033
- Hanahan, Hallmarks of Cancer: New Dimensions (Cancer Discovery 2022): https://doi.org/10.1158/2159-8290.CD-21-1059

## Connected records

- pathways: [Clonal evolution & minimal residual disease](https://onco.cc/pathways/clonal-evolution/), [Drug efflux pumps (ABC transporters)](https://onco.cc/pathways/drug-efflux-pumps/), [Drug-tolerant persister cells](https://onco.cc/pathways/drug-tolerant-persisters/), [Epigenetic reprogramming](https://onco.cc/pathways/epigenetic-reprogramming/), [Epithelial-mesenchymal transition & drug efflux](https://onco.cc/pathways/emt/), [Hedgehog signalling](https://onco.cc/pathways/hedgehog/), [Lineage plasticity & neuroendocrine transformation](https://onco.cc/pathways/lineage-plasticity-neuroendocrine/), [Notch signalling](https://onco.cc/pathways/notch/), [SWI/SNF chromatin remodelling](https://onco.cc/pathways/swi-snf-chromatin/), [Theories of cancer: how the ideas connect](https://onco.cc/pathways/theories-of-cancer/), [Wnt / β-catenin](https://onco.cc/pathways/wnt/)
- terms: [Cancer stem cell theory and phenotypic plasticity](https://onco.cc/terms/cancer-stem-cell-theory/), [Differentiation](https://onco.cc/terms/differentiation/), [Hallmark (2022): unlocking phenotypic plasticity](https://onco.cc/terms/unlocking-phenotypic-plasticity/), [Histologic transformation](https://onco.cc/terms/histologic-transformation/), [LGR5](https://onco.cc/terms/lgr5/), [Stem cell](https://onco.cc/terms/stem-cell/)
- targets: [DLL3](https://onco.cc/targets/dll3/), [EZH2](https://onco.cc/targets/ezh2/), [Menin](https://onco.cc/targets/menin/), [RB1](https://onco.cc/targets/rb1/), [TP53](https://onco.cc/targets/tp53/)
- drugs: [Revumenib](https://onco.cc/drugs/revumenib/), [Tarlatamab](https://onco.cc/drugs/tarlatamab/)
- institutions: [Memorial Sloan Kettering Cancer Center](https://onco.cc/institutions/mskcc/), [Princess Margaret Cancer Centre](https://onco.cc/institutions/princess-margaret/), [Stanford Health Care / Stanford Cancer Institute](https://onco.cc/institutions/stanford/), [The Francis Crick Institute](https://onco.cc/institutions/francis-crick/)
- key papers: [Hallmarks of Cancer 2022: adding phenotypic plasticity, epigenetic reprogramming, microbiomes and senescent cells](https://onco.cc/key-papers/paper-hallmarks-new-dimensions-cancer-discov-2022/), [Impact of Lineage Plasticity to and from a Neuroendocrine Phenotype on Progression and Response in Prostate and Lung Cancers](https://onco.cc/key-papers/paper-rubin-mol-cell/), [Singh 2004: identification of human brain tumour initiating cells](https://onco.cc/key-papers/paper-singh-brain-tumour-initiating-cells-nature-2004/), [SOX2 promotes lineage plasticity and antiandrogen resistance in TP53- and RB1-deficient prostate cancer](https://onco.cc/key-papers/paper-mu-sox2-lineage-plasticity-science-2017/), [Stromal gene expression defines poor-prognosis subtypes in colorectal cancer](https://onco.cc/key-papers/paper-calon-stromal-gene-expression-poor-prognosis-colorectal-nat-genet-2015/)

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