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<p>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<sup>med</sup> (Lin<sup>-</sup>, Sca-1<sup>+</sup>, CD49f<sup>med</sup>) 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<sup>med</sup> cells isolated from prostate-specific <i>Pten</i>-deficient (<i>Pten</i><sup><i>pc−/−</i></sup>) mice, we identify the emergence of castration-resistant LSC<sup>med</sup> cells enriched in stem-like features, driven by the transcription factor FOSL1/AP-1. We demonstrate that cells exhibiting <i>Pten</i><sup><i>pc−/−</i></sup> LSC<sup>med</sup> 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.</p>

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Targeting pre-existing club-like cells in prostate cancer potentiates androgen deprivation therapy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月2日

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  • 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

摘要

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.