https://phaidra.vetmeduni.ac.at/o:5419 Targeting pre-existing club-like cells in prostate cancer potentiates androgen deprivation therapy Baurès, Manon Manon Baurès University of Veterinary Medicine Vienna. Shared Facility Bioinformatics and Biostatistics Vieira Aleixo, Anne-Sophie Anne-Sophie Vieira Aleixo Pacreau, Emeline Emeline Pacreau University of Veterinary Medicine Vienna. Clinical Department for Small Animals and Horses Koshy, Aysis Aysis Koshy 0009-0006-5478-8544 Friedrich, Vanessa Vanessa Friedrich 0009-0007-4585-7971 Diedisheim, Marc Marc Diedisheim 0000-0002-0418-1107 Raigel, Martin Martin Raigel Hua, Yichao Yichao Hua 0000-0002-1695-172X Dariane, Charles Charles Dariane Boutillon, Florence Florence Boutillon Kenner, Lukas Lukas Kenner 0000-0003-2184-1338 University of Veterinary Medicine Vienna. Clinical Department for Farm Animals and Food System Transformation Marine, Jean-Christophe Jean-Christophe Marine Laverny, Gilles Gilles Laverny 0000-0002-2666-6877 Metzger, Daniel Daniel Metzger 0000-0002-5555-046X Rambow, Florian Florian Rambow 0000-0002-9727-8986 Guidotti, Jacques-Emmanuel Jacques-Emmanuel Guidotti 0000-0001-9285-8167 Goffin, Vincent Vincent Goffin 0000-0002-8021-3086 University of Veterinary Medicine Vienna. Shared Facility Bioinformatics and Biostatistics journal article open access eng 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 LSCmed (Lin-, Sca-1+, CD49fmed) 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 LSCmed cells isolated from prostate-specific Pten-deficient (Ptenpc−/−) mice, we identify the emergence of castration-resistant LSCmed cells enriched in stem-like features, driven by the transcription factor FOSL1/AP-1. We demonstrate that cells exhibiting Ptenpc−/− LSCmed 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. Castration-Resistance Club Cells DNPC FOSL1 LSCmed Cells http://creativecommons.org/licenses/by/4.0/ https://phaidra.vetmeduni.ac.at/api/object/o:5419/download 10.1038/s44321-026-00375-y https://phaidra.vetmeduni.ac.at/o:605 application/pdf EMBO Molecular Medicine issn:1757-4684 VoR EMBO Molecular Medicine 18 3 12.25 MB 2026