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
Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109.
Department of Pathology, University of Michigan, Ann Arbor, MI 48109.
Proc Natl Acad Sci U S A. 2025 Sep 2;122(35):e2427116122. doi: 10.1073/pnas.2427116122. Epub 2025 Aug 25.
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.
前列腺癌中经常出现对雄激素剥夺疗法（ADT）反应不足的情况，其背后的细胞机制仍知之甚少。在这里，我们整合了单细胞RNA测序、单细胞多组学和空间转录组学，以确定小鼠前列腺中细胞身份和去势反应的转录、表观遗传和空间基础。利用这些数据以及对人类前列腺和前列腺癌（PCa）的荟萃分析，我们确定了ADT反应和耐药性的细胞直系同源物和关键决定因素。我们的研究结果表明，小鼠前列腺含有叶特异性管腔上皮细胞类型，其特征是独特的基因调控模块和解剖学定义的雄激素反应性转录程序，这表明其发育起源不同。雄激素不敏感的、类似干细胞的上皮群体——类似于人类的俱乐部细胞和小丘细胞——在尿道和腹侧前列腺中显著富集，但在其他叶中很少见。在腹侧前列腺内，我们还发现了另外两种雄激素反应性管腔上皮细胞类型，以Pbsn或Spink1表达为特征，它们与人类管腔亚群一致，可能定义了不同PCa亚型的起源。去势深刻地重塑了管腔上皮转录组，去势抵抗性管腔上皮细胞激活了应激反应和干性程序。这些转录特征在接受ADT治疗和去势抵抗性PCa患者的肿瘤细胞中富集，强调了它们在驱动治疗抵抗中的可能作用。对细胞的时间追踪将精确绘制与疾病相关的细胞转变，我们的技术框架有助于进行此类研究。总的来说，我们全面的小鼠前列腺细胞图谱阐明了叶特异性背景对PCa建模的重要性，并揭示了对抗去势抵抗的潜在治疗靶点
