Cellular cartography reveals mouse prostate organization and determinants of castration resistance

• 成果类型: Article
• 署名作者: Cho, Hanbyul; Zhang, Yuping; Tien, Jean C.; Mannan, Rahul; Luo, Jie; Narayanan, Sathiya Pandi; Mahapatra, Somnath; Hu, Jing; Shelley, Greg; Cruz, Gabriel; Shahine, Miriam; Wang, Lisha; Su, Fengyun; Wang, Rui; Cao, Xuhong; Dhanasekaran, Saravana Mohan; Keller, Evan T.; Pitchiaya, Sethuramasundaram; Chinnaiyan, Arul M.
• 署名单位: University of Michigan System; University of Michigan; University of Michigan System; University of Michigan; University of Michigan System; University of Michigan; Shandong University; University of Michigan System; University of Michigan; University of Michigan System; University of Michigan; University of Michigan System; University of Michigan; University of Michigan System; University of Michigan; Howard Hughes Medical Institute; University of Michigan System; University of Michigan
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12867
• DOI: 10.1073/pnas.2427116122
• 发表日期: 2025-09-02
• 关键词: androgen receptor protein; stem-cells; transcription factors; increased survival; messenger-rna; cancer; expression; progression; origin; murine

摘要

Inadequate response to androgen deprivation therapy (ADT) frequently arises in prostate cancer, driven by cellular mechanisms that remain poorly understood. Here, we integrated single- cell RNA sequencing, single- cell multiomics, and spatial transcriptomics to define the transcriptional, epigenetic, and spatial basis of cell identity and castration response in the mouse prostate. Leveraging these data along with a meta- analysis of human prostates and prostate cancer (PCa), we identified cellular orthologs and key determinants of ADT response and resistance. Our findings reveal that mouse prostates harbor lobe- specific luminal epithelial cell types distinguished by unique gene regulatory modules and anatomically defined androgen- responsive transcriptional programs, indicative of divergent developmental origins. Androgen- insensitive, stem- like epithelial populations-resembling human club and hillock cells-are notably enriched in the urethra and ventral prostate but are rare in other lobes. Within the ventral prostate, we also uncovered two additional androgen- responsive luminal epithelial cell types, marked by Pbsn or Spink1 expression, which align with human luminal subsets and may define the origin of distinct PCa subtypes. Castration profoundly reshaped luminal epithelial transcriptomes, with castration- resistant luminal epithelial cells activating stress- responsive and stemness programs. These transcriptional signatures are enriched in tumor cells from ADT- treated and castration- resistant PCa patients, underscoring their likely role in driving treatment resistance. Temporal tracking of cells will precisely map disease- associated cellular transitions, and our technical framework facilitates such interrogations. Collectively, our comprehensive cellular atlas of the mouse prostate illuminates the importance of lobe- specific contexts for PCa modeling and reveals potential therapeutic targets to counter castration resistance.