Oncofetal reprogramming drives phenotypic plasticity in WNT-dependent colorectal cancer
Targeting cancer stem cells (CSCs) is crucial for effective cancer treatment, yet resistance mechanisms to LGR5<sup>+</sup> 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<sup>+</sup> states in isolation is constrained by their functional redundancy. Although the canonical LGR5<sup>+</sup> 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.
Authors
- Gulay Ulukaya
- Deniz Demircioğlu (ORCID: https://orcid.org/0000-0001-7857-0407)
- Jean‐Christophe Marine (ORCID: https://orcid.org/0000-0003-2433-9837)
- Lewis E. Tomalin (ORCID: https://orcid.org/0000-0003-4545-7138)
- Federico Di Tullio (ORCID: https://orcid.org/0000-0001-9756-976X)
- Peter Vermeulen (ORCID: https://orcid.org/0000-0002-5676-3141)
- Kevin Mohammed (ORCID: https://orcid.org/0000-0002-9955-9407)
- Daniel Lozano‐Ojalvo (ORCID: https://orcid.org/0000-0002-3524-2929)
- Denis Torre (ORCID: https://orcid.org/0000-0003-4615-223X)
- Marc Leushacke
- Bruno Giotti (ORCID: https://orcid.org/0000-0001-8102-5266)
- Megan Schwarz (ORCID: https://orcid.org/0000-0001-8715-2039)
- Tamsin R.M. Lannagan (ORCID: https://orcid.org/0000-0002-8206-8898)
- Panagiotis Karras (ORCID: https://orcid.org/0000-0002-7642-0875)
- Owen J. Sansom (ORCID: https://orcid.org/0000-0001-9540-3010)
- Alexander M. Tsankov (ORCID: https://orcid.org/0000-0002-7955-4414)
- Ernesto Guccione (ORCID: https://orcid.org/0000-0001-7764-5307)
- Nick Barker (ORCID: https://orcid.org/0000-0003-3566-4475)
- Xuedi Wang (ORCID: https://orcid.org/0009-0000-7238-745X)
- Habiba Zorgati (ORCID: https://orcid.org/0000-0001-9840-7156)
- Robert Sebra (ORCID: https://orcid.org/0000-0001-9267-2426)
- Yuliia Dramaretska (ORCID: https://orcid.org/0000-0002-9792-0465)
- Gaetano Gargiulo (ORCID: https://orcid.org/0000-0001-5414-4251)
- Slim Mzoughi (ORCID: https://orcid.org/0000-0002-5158-0389)
- Dan Hasson (ORCID: https://orcid.org/0000-0001-7943-1636)
Institutions
- Agency for Science, Technology and Research (SG)
- National University of Singapore (SG)
- Max Delbrück Center (DE)
- Cancer Research UK (GB)
- VIB-KU Leuven Center for Cancer Biology (BE)
- Institute of Molecular and Cell Biology (SG)
- University of Glasgow (GB)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- Nature Genetics
- Published
- 2025-02-01
- DOI
- https://doi.org/10.1038/s41588-024-02058-1
- Citations
- 39
- Primary Topic
- Cancer Cells and Metastasis
- Type
- article
- Field-Weighted Citation Impact
- 40.77