Journal Article

Oncofetal reprogramming drives phenotypic plasticity in WNT-dependent colorectal cancer

Lannagan, Tamsin RM, Sebra, Robert, Demircioglu, Deniz, Di Tullio, Federico, Leushacke, Marc, Mzoughi, Slim, Schwarz, Megan, Ulukaya, Gulay, Tsankov, Alexander M., Vermeulen, Peter B., Barker, Nick, Zorgati, Habiba, Gargiulo, Gaetano, Company, Carlos, Torre, Denis, Hasson, Dan, Guccione, Ernesto, Giotti, Bruno, Sansom, Owen J., Tomalin, Lewis E., Dramaretska, Yuliia, Karras, Panagiotis, Lozano-Ojalvo, Daniel, Marine, Jean-Christophe, Wang, Xuedi, Mohammed, Kevin

2025

Overview

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. Oncofetal (OnF) reprogramming, driven by YAP and AP-1, induces phenotypic plasticity and therapy resistance in WNT-dependent colorectal cancer (CRC). Targeting the OnF state in combination with chemotherapy substantially attenuates tumor growth in mouse models and patient-derived CRC tumoroids.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/337/176 / 631/67/1504 / Adenomatous polyposis coli / Agriculture / Animal Genetics and Genomics / Animals / Biomedical and Life Sciences / Biomedicine / Cancer / Cancer Research / Cancer therapies / Cell Plasticity - genetics / Cellular Reprogramming - genetics / Colorectal cancer / Colorectal Neoplasms - drug therapy / Colorectal Neoplasms - genetics / Colorectal Neoplasms - metabolism / Colorectal Neoplasms - pathology / Deregulation / Drug Resistance, Neoplasm - genetics / Female / Fluorouracil - pharmacology / Gene Function / Human Genetics / Humans / Mice / Mutation / Neoplastic Stem Cells - drug effects / Neoplastic Stem Cells - metabolism / Neoplastic Stem Cells - pathology / Phenotype / Phenotypic plasticity / Plastic properties / Plasticity / Polyposis coli / Polyps / Receptors, G-Protein-Coupled - genetics / Receptors, G-Protein-Coupled - metabolism / Redundancy / Stem cells / Transcription factors / Tumors / Wnt protein / Wnt Signaling Pathway - genetics / Yes-associated protein