Targeting pre-existing club-like cells in prostate cancer potentiates androgen deprivation therapy
Year: 2026
Type: article
Abstract: 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 med (Lin - , Sca-1 + , CD49f med ) 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 med cells isolated from prostate-specific Pten -deficient ( Pten pc−/− ) mice, we identify the emergence of castration-resistant LSC med cells enriched in stem-like features, driven by the transcription factor FOSL1/AP-1. We demonstrate that cells exhibiting Pten pc−/− LSC med 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.
Source: EMBO Molecular Medicine
Authors: Manon Baurès, Anne-Sophie Vieira Aleixo, Emeline Pacreau, Aysis Koshy, Vanessa Friedrich, Marc Diedisheim, Martin Raigel, Yichao Hua, Charles Dariane, Florence Boutillon, Lukas Kenner, Jean-Christophe Marine, Gilles Laverny, Daniel Metzger, Florian Rambow, Jacques-Emmanuel Guidotti, Vincent Goffin
Institutions: Centre National de la Recherche Scientifique, Inserm, Université Paris Cité, Institut Necker Enfants Malades, Institut de génétique et de biologie moléculaire et cellulaire, Université de Strasbourg, University of Veterinary Medicine Vienna, Medical University of Vienna, Essen University Hospital, University of Duisburg-Essen, Assistance Publique – Hôpitaux de Paris, Hôpital Européen Georges-Pompidou, Structure Fédérative de Recherche en Biologie et Santé de Rennes, Université de Rennes, Comprehensive Cancer Center Vienna, Center For Biomarker Research In Medicine, Umeå University, VIB-KU Leuven Center for Cancer Biology, KU Leuven
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $7,990
Funders: Alliance Nationale pour les Sciences de la Vie et de la Santé, Agence Nationale de la Recherche, Institut National de la Santé et de la Recherche Médicale, Université de Strasbourg, Ligue Contre le Cancer, Centre National de la Recherche Scientifique, Institut National Du Cancer, Association pour la Recherche sur les Tumeurs de la Prostate
Awards: G1190173965, G164444715, Par-delà les frontières, l'Université de Strasbourg, G2255650664, Organisation et montée en puissance d'une Infrastructure Nationale de Génomique, G2659019386, G2694206344, Façonner les talents en formation et en recherche à l'Université de Strasbourg, G2980570810, Identification, characterization and therapeutic targeting of castration-resistant prostatic luminal progenitor cells, G3357951378, G3730343, G399734812, Integrative Molecular and Cellular Biology, G471331628, G4779185514, G5766795845, G6136357505, G6276897512, G6803667113, G7240651115
OpenAlex ID: W7127128349