Oncofetal Reprogramming Drives Phenotypic Plasticity in WNT-dependent Colorectal Cancer

Overview

Journal Nat Genet

Date 2025 Feb 10

PMID 39930084

Authors

Slim Mzoughi

Megan Schwarz

Xuedi Wang

Deniz Demircioglu

Gulay Ulukaya

Kevin Mohammed

Habiba Zorgati

Denis Torre

Lewis E Tomalin

Federico Di Tullio

Carlos Company

Yuliia Dramaretska

Marc Leushacke

Bruno Giotti

Tamsin Rm Lannagan

Daniel Lozano-Ojalvo

Panagiotis Karras

Peter B Vermeulen

Dan Hasson

Robert Sebra

Alexander M Tsankov

Owen J Sansom

Jean-Christophe Marine

Nick Barker

Gaetano Gargiulo

Ernesto Guccione

Affiliations

Soon will be listed here.

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.

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