{"entity":{"id":"cancer-stem-cells-plasticity","kind":"pathway","name":"Cancer stem cells & phenotypic plasticity","aka":[],"tldr":"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.","asOf":"2026-09-08","wikipedia":"https://en.wikipedia.org/wiki/Cancer_stem_cell","links":[{"label":"Rubin, Bristow, Thienger et al., Impact of lineage plasticity to and from a neuroendocrine phenotype (Molecular Cell 2020)","url":"https://doi.org/10.1016/j.molcel.2020.10.033"},{"label":"Hanahan, Hallmarks of Cancer: New Dimensions (Cancer Discovery 2022)","url":"https://doi.org/10.1158/2159-8290.CD-21-1059"}],"tags":["mechanism"],"related":["theories-of-cancer","cancer-stem-cell-theory"],"cancers":[],"sections":[],"technologies":[],"targets":["ezh2","dll3","menin","tp53"],"drugs":["tarlatamab","revumenib"],"companies":[],"institutions":["princess-margaret","mskcc","stanford","francis-crick"],"pathways":["emt","wnt","notch","hedgehog","swi-snf-chromatin","clonal-evolution"],"terms":["unlocking-phenotypic-plasticity","histologic-transformation","lgr5"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-singh-brain-tumour-initiating-cells-nature-2004","paper-rubin-mol-cell"],"journals":[],"dependsOn":[],"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)."],"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.","nodes":[{"id":"csc","label":"Stem-like state","x":50,"y":30},{"id":"diff","label":"Differentiated bulk","x":20,"y":60},{"id":"mes","label":"Mesenchymal / drug-tolerant persister","x":80,"y":60},{"id":"ne","label":"Lineage switch (NE transformation)","x":50,"y":88,"targetId":"dll3"},{"id":"epi","label":"EZH2, SWI/SNF, TP53/RB1 loss","x":88,"y":20,"targetId":"ezh2"},{"id":"niche","label":"Wnt / Notch / Hedgehog niche","x":12,"y":20}],"edges":[{"from":"csc","to":"diff","type":"activates"},{"from":"diff","to":"csc","type":"activates"},{"from":"csc","to":"mes","type":"activates"},{"from":"mes","to":"csc","type":"activates"},{"from":"epi","to":"ne","type":"activates"},{"from":"csc","to":"ne","type":"activates"},{"from":"niche","to":"csc","type":"activates"},{"from":"epi","to":"csc","type":"activates"}],"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"]},"route":"/pathways/cancer-stem-cells-plasticity/","neighbours":{"pathway":[{"id":"clonal-evolution","kind":"pathway","name":"Clonal evolution & minimal residual disease","route":"/pathways/clonal-evolution/"},{"id":"drug-efflux-pumps","kind":"pathway","name":"Drug efflux pumps (ABC transporters)","route":"/pathways/drug-efflux-pumps/"},{"id":"drug-tolerant-persisters","kind":"pathway","name":"Drug-tolerant persister cells","route":"/pathways/drug-tolerant-persisters/"},{"id":"epigenetic-reprogramming","kind":"pathway","name":"Epigenetic reprogramming","route":"/pathways/epigenetic-reprogramming/"},{"id":"emt","kind":"pathway","name":"Epithelial-mesenchymal transition & drug efflux","route":"/pathways/emt/"},{"id":"hedgehog","kind":"pathway","name":"Hedgehog signalling","route":"/pathways/hedgehog/"},{"id":"lineage-plasticity-neuroendocrine","kind":"pathway","name":"Lineage plasticity & neuroendocrine transformation","route":"/pathways/lineage-plasticity-neuroendocrine/"},{"id":"notch","kind":"pathway","name":"Notch signalling","route":"/pathways/notch/"},{"id":"swi-snf-chromatin","kind":"pathway","name":"SWI/SNF chromatin remodelling","route":"/pathways/swi-snf-chromatin/"},{"id":"theories-of-cancer","kind":"pathway","name":"Theories of cancer: how the ideas connect","route":"/pathways/theories-of-cancer/"},{"id":"wnt","kind":"pathway","name":"Wnt / β-catenin","route":"/pathways/wnt/"}],"term":[{"id":"cancer-stem-cell-theory","kind":"term","name":"Cancer stem cell theory and phenotypic plasticity","route":"/terms/cancer-stem-cell-theory/"},{"id":"differentiation","kind":"term","name":"Differentiation","route":"/terms/differentiation/"},{"id":"unlocking-phenotypic-plasticity","kind":"term","name":"Hallmark (2022): unlocking phenotypic plasticity","route":"/terms/unlocking-phenotypic-plasticity/"},{"id":"histologic-transformation","kind":"term","name":"Histologic transformation","route":"/terms/histologic-transformation/"},{"id":"lgr5","kind":"term","name":"LGR5","route":"/terms/lgr5/"},{"id":"stem-cell","kind":"term","name":"Stem cell","route":"/terms/stem-cell/"}],"target":[{"id":"dll3","kind":"target","name":"DLL3","route":"/targets/dll3/"},{"id":"ezh2","kind":"target","name":"EZH2","route":"/targets/ezh2/"},{"id":"menin","kind":"target","name":"Menin","route":"/targets/menin/"},{"id":"rb1","kind":"target","name":"RB1","route":"/targets/rb1/"},{"id":"tp53","kind":"target","name":"TP53","route":"/targets/tp53/"}],"drug":[{"id":"revumenib","kind":"drug","name":"Revumenib","route":"/drugs/revumenib/"},{"id":"tarlatamab","kind":"drug","name":"Tarlatamab","route":"/drugs/tarlatamab/"}],"institution":[{"id":"mskcc","kind":"institution","name":"Memorial Sloan Kettering Cancer Center","route":"/institutions/mskcc/"},{"id":"princess-margaret","kind":"institution","name":"Princess Margaret Cancer Centre","route":"/institutions/princess-margaret/"},{"id":"stanford","kind":"institution","name":"Stanford Health Care / Stanford Cancer Institute","route":"/institutions/stanford/"},{"id":"francis-crick","kind":"institution","name":"The Francis Crick Institute","route":"/institutions/francis-crick/"}],"paper":[{"id":"paper-hallmarks-new-dimensions-cancer-discov-2022","kind":"paper","name":"Hallmarks of Cancer 2022: adding phenotypic plasticity, epigenetic reprogramming, microbiomes and senescent cells","route":"/key-papers/paper-hallmarks-new-dimensions-cancer-discov-2022/"},{"id":"paper-rubin-mol-cell","kind":"paper","name":"Impact of Lineage Plasticity to and from a Neuroendocrine Phenotype on Progression and Response in Prostate and Lung Cancers","route":"/key-papers/paper-rubin-mol-cell/"},{"id":"paper-singh-brain-tumour-initiating-cells-nature-2004","kind":"paper","name":"Singh 2004: identification of human brain tumour initiating cells","route":"/key-papers/paper-singh-brain-tumour-initiating-cells-nature-2004/"},{"id":"paper-mu-sox2-lineage-plasticity-science-2017","kind":"paper","name":"SOX2 promotes lineage plasticity and antiandrogen resistance in TP53- and RB1-deficient prostate cancer","route":"/key-papers/paper-mu-sox2-lineage-plasticity-science-2017/"},{"id":"paper-calon-stromal-gene-expression-poor-prognosis-colorectal-nat-genet-2015","kind":"paper","name":"Stromal gene expression defines poor-prognosis subtypes in colorectal cancer","route":"/key-papers/paper-calon-stromal-gene-expression-poor-prognosis-colorectal-nat-genet-2015/"}]}}