Understanding prostate response to castration and androgen receptor signaling inhibitors (ARSI) is critical to improving long-term prostate cancer (PCa) patient survival. Here, we use a multi-omics approach on 229,794 single cells to create a mouse single-cell reference atlas for interpreting mouse prostate biology and castration response. Our reference atlas refines single-cell annotations and provides a chromatin context, which, when coupled with mouse lineage tracing, demonstrates that castration-resistant luminal cells are distinct from the pre-existent urethra-proximal stem/progenitor cells. Molecular pathway analysis and therapeutic studies further implicate AP1 (JUN/FOS), WNT/β-catenin, FOXQ1, NF-κB, and JAK/STAT pathways as major drivers of castration-resistant luminal populations with relevance to human PCa. Our datasets, which can be explored through an interactive portal (https://visportal.roswellpark.org/data/tang/), can aid in developing combination treatments with ARSI for advanced PCa patients.

了解前列腺对去势和雄激素受体信号抑制剂 (ARSI) 的反应对于改善前列腺癌 (PCa) 患者的长期生存至关重要。在这里，我们对 229,794 个单细胞使用多组学方法来创建小鼠单细胞参考图谱，用于解释小鼠前列腺生物学和去势反应。我们的参考图谱完善了单细胞注释并提供了染色质背景，当与小鼠谱系追踪相结合时，证明去势抵抗性管腔细胞与预先存在的尿道近端干/祖细胞不同。分子通路分析和治疗研究进一步表明 AP1 (JUN/FOS)、WNT/β-连环蛋白、FOXQ1、NF-κB 和 JAK/STAT 通路是与人类 PCa 相关的去势抵抗管腔群体的主要驱动因素。我们的数据集，可以通过交互式门户进行探索（ https://visportal.roswellpark.org/data/tang/ ），可以帮助开发与 ARSI 联合治疗晚期 PCa 患者。