Oncofetal reprogramming drives phenotypic plasticity in WNT-dependent colorectal cancer

Mzoughi, S.; Schwarz, M.; Wang, X.; Demircioglu, D.; Ulukaya, G.; Mohammed, K.; Zorgati, H.; Torre, D.; Tomalin, L.E.; Di Tullio, F.; Company, C.; Dramaretska, Y.; Leushacke, M.; Giotti, B.; Lannagan, T.R.; Lozano-Ojalvo, D.; Karras, P.; Vermeulen, P.B.; Hasson, D.; Sebra, R.; Tsankov, A.M.; Sansom, O.J.; Marine, J.C.; Barker, N.; Gargiulo, G.; Guccione, E.

Oncofetal reprogramming drives phenotypic plasticity in WNT-dependent colorectal cancer

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Item Type:	Article
Title:	Oncofetal reprogramming drives phenotypic plasticity in WNT-dependent colorectal cancer
Creators Name:	Mzoughi, S., Schwarz, M., Wang, X., Demircioglu, D., Ulukaya, G., Mohammed, K., Zorgati, H., Torre, D., Tomalin, L.E., Di Tullio, F., Company, C., Dramaretska, Y., Leushacke, M., Giotti, B., Lannagan, T.R., Lozano-Ojalvo, D., Karras, P., Vermeulen, P.B., Hasson, D., Sebra, R., Tsankov, A.M., Sansom, O.J., Marine, J.C., Barker, N., Gargiulo, G. and Guccione, E.
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.
Keywords:	Adenomatous Polyposis Coli Protein, Antineoplastic Combined Chemotherapy Protocols, Camptothecin, Cellular Reprogramming, Colorectal Neoplasms, Fluorouracil, G-Protein-Coupled Receptors, Leucovorin, Neoplasm Drug Resistance, Neoplastic Stem Cells, Phenotype, Wnt Signaling Pathway, Animals, Mice
Source:	Nature Genetics
ISSN:	1061-4036
Publisher:	Nature Publishing Group
Volume:	57
Number:	2
Page Range:	402-412
Date:	February 2025
Official Publication:	https://doi.org/10.1038/s41588-024-02058-1
PubMed:	View item in PubMed

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