Oncofetal reprogramming drives phenotypic plasticity in WNT-dependent colorectal cancer
Authors
- S. Mzoughi
- M. Schwarz
- X. Wang
- D. Demircioglu
- G. Ulukaya
- K. Mohammed
- H. Zorgati
- D. Torre
- L.E. Tomalin
- F. Di Tullio
- C. Company
- Y. Dramaretska
- M. Leushacke
- B. Giotti
- T.R. Lannagan
- D. Lozano-Ojalvo
- P. Karras
- P.B. Vermeulen
- D. Hasson
- R. Sebra
- A.M. Tsankov
- O.J. Sansom
- J.C. Marine
- N. Barker
- G. Gargiulo
- E. Guccione
Journal
- Nature Genetics
Citation
- Nat Genet 57 (2): 402-412
Abstract
Targeting cancer stem cells (CSCs) is crucial for effective cancer treatment, yet resistance mechanisms to LGR5(+) CSC depletion in WNT-driven colorectal cancer (CRC) remain elusive. In the present study, we revealed that mutant intestinal stem cells (SCs) depart from their canonical identity, traversing a dynamic phenotypic spectrum. This enhanced plasticity is initiated by oncofetal (OnF) reprogramming, driven by YAP and AP-1, with subsequent AP-1 hyperactivation promoting lineage infidelity. The retinoid X receptor serves as a gatekeeper of OnF reprogramming and its deregulation after adenomatous polyposis coli (APC) loss of function establishes an OnF ‘memory’ sustained by YAP and AP-1. Notably, the clinical significance of OnF and LGR5(+) states in isolation is constrained by their functional redundancy. Although the canonical LGR5(+) state is sensitive to the FOLFIRI regimen, an active OnF program correlates with resistance, supporting its role in driving drug-tolerant states. Targeting this program in combination with the current standard of care is pivotal for achieving effective and durable CRC treatment.