Cancer stem cells & phenotypic plasticity
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.
Cancer stem cells (CSCs; first shown in AML by Dick, 1994-97) are functionally defined by tumour-initiating capacity; in many solid tumours stemness is 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.
In one picture
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.
Diagram
top- 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
top- 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).