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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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