par Mzoughi, Slim;Schwarz, Megan;Wang, Xuedi;Demircioglu, Deniz;Ulukaya, Gulay;Mohammed, Kevin;Zorgati, Habiba;Torre, Denis;Tomalin, Lewis Elwood;Di Tullio, Federico;Company, Carlos;Dramaretska, Yuliia;Leushacke, Marc;Giotti, Bruno;Lannagan, Tamsin Rosemary Margaret;Lozano-Ojalvo, Daniel;Karras, Panagiotis 
;Vermeulen, Peter B.;Hasson, Dan;Sebra, Robert;Tsankov, Alexander A.M.;Sansom, Owen;Marine, Jean-Christophe ;Barker, Nick;Gargiulo, Gaetano;Guccione, Ernesto
Référence Nature genetics, 57, 2, page (402-412), 3464
Publication Publié, 2025-02-01
;Vermeulen, Peter B.;Hasson, Dan;Sebra, Robert;Tsankov, Alexander A.M.;Sansom, Owen;Marine, Jean-Christophe ;Barker, Nick;Gargiulo, Gaetano;Guccione, ErnestoRéférence Nature genetics, 57, 2, page (402-412), 3464
Publication Publié, 2025-02-01
Article révisé par les pairs
| Résumé : | 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. |
