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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.


DOI

doi:10.1038/s41588-024-02058-1