了解前列腺对去势和雄激素受体信号抑制剂（ARSI）的反应对提高长期前列腺癌（PCa）患者的生存率至关重要。在这里，我们利用多组学方法对229，794个单细胞进行研究，以创建一份更适合解释小鼠前列腺生物学和去势反应的小鼠单细胞参考图谱。我们的参考图谱精细化了单细胞注释，并提供了染色体的上下文，当结合小鼠谱系追踪时，证明去势耐受的壁细胞与先前存在的尿道近端干/祖细胞有所不同。分子通路分析和治疗研究进一步证明，JUN/FOS、WNT/B-Catenin、FOXQ1、NFKB和JAK/STAT通路是导致耐受去势的壁细胞群体的主要驱动因素，并与人类PCa具有高度相关性。重要的是，我们展示了我们的数据集的实用性，可以通过交互式门户网站（https://visportal.roswellpark.org/data/tang/）进行探索，以帮助开发新的与ARSI组合治疗方案，用于晚期PCa患者。

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 better suited to interpreting mouse prostate biology and castration response. Our reference atlas refines single-cell annotations and provides chromatin context, which, when coupled with mouse lineage tracing demonstrates that the castration-resistant luminal cells are distinct from the pre-existent urethra-proximal stem/progenitor cells. Molecular pathway analysis and therapeutic studies further implicate JUN/FOS, WNT/B-Catenin, FOXQ1, NFkB, and JAK/STAT pathways as the major drivers of castration-resistant luminal populations with high relevance to human PCa. Importantly, we demonstrate the utility of our datasets, which can be explored through an interactive portal (https://visportal.roswellpark.org/data/tang/), to aid in developing novel combination treatments with ARSI for advanced PCa patients.