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Date publication
février 2026
Journal
EMBO molecular medicine
Auteurs
Membres identifiés du Cancéropôle Est :
Dr METZGER Daniel
,
Dr LAVERNY Gilles
Tous les auteurs :
Baurès M, Vieira Aleixo AS, Pacreau E, Koshy A, Friedrich V, Diedisheim M, Raigel M, Hua Y, Dariane C, Boutillon F, Kenner L, Marine JC, Laverny G, Metzger D, Rambow F, Guidotti JE, Goffin V
Lien Pubmed
Résumé
A critical knowledge gap in prostate cancer research is understanding whether castration-tolerant progenitor-like cells that reside in treatment-naïve tumors play a direct role in therapy resistance and tumor progression. Herein, we reveal that the castration tolerance of LSC (Lin, Sca-1, CD49f) progenitor cells, the mouse equivalent of human prostatic Club cells, arises not from intrinsic properties, but from significant transcriptional reprogramming. Utilizing single-cell RNA sequencing of LSC cells isolated from prostate-specific Pten-deficient (Pten) mice, we identify the emergence of castration-resistant LSC cells enriched in stem-like features, driven by the transcription factor FOSL1/AP-1. We demonstrate that cells exhibiting Pten LSC characteristics are prevalent in aggressive double-negative prostate cancer (DNPC) subtypes recently identified in human castration-resistant prostate cancer (CRPC). Furthermore, our findings show that the dual-targeting agents JQ-1 and CX-6258-focused on FOSL1/AP-1 and PIM kinases, respectively-effectively suppress both the progenitor properties and the growth of mouse and human DNPC surrogates in vitro and in vivo. Thus, early eradication of castration-tolerant Club-like cells presents a promising therapeutic strategy to mitigate prostate cancer progression toward CRPC.
Mots clés
Castration-Resistance, Club Cells, DNPC, FOSL1, LSCmed Cells
Référence
EMBO Mol Med. 2026 02 2;:
