Oncofetal reprogramming drives phenotypic plasticity in WNT-dependent colorectal cancer.

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 const

SUBMITTER: Mzoughi S 

PROVIDER: S-EPMC11821538 | biostudies-literature | 2025 Feb

REPOSITORIES: biostudies-literature