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| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Artículo científico |
| Language: | en |
| Published: |
Nature genetics
2025
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| Subjects: | |
| Online Access: | https://pubmed.ncbi.nlm.nih.gov/39930084/ |
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Table of Contents:
- Oncofetal reprogramming drives phenotypic plasticity in WNT-dependent colorectal cancer. Mzoughi, Slim Schwarz, Megan Wang, Xuedi Demircioglu, Deniz Ulukaya, Gulay Mohammed, Kevin Zorgati, Habiba Torre, Denis Tomalin, Lewis E Di Tullio, Federico Company, Carlos Dramaretska, Yuliia Leushacke, Marc Giotti, Bruno Lannagan, Tamsin Rm Lozano-Ojalvo, Daniel Karras, Panagiotis Vermeulen, Peter B Hasson, Dan Sebra, Robert Tsankov, Alexander M Sansom, Owen J Marine, Jean-Christophe Barker, Nick Gargiulo, Gaetano Guccione, Ernesto Colorectal Neoplasms Humans Animals Neoplastic Stem Cells Mice Cellular Reprogramming Wnt Signaling Pathway Phenotype Receptors, G-Protein-Coupled Cell Plasticity Drug Resistance, Neoplasm Fluorouracil Female 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.