Integrated single-cell analysis defines the epigenetic basis of castration-resistant prostate luminal cells.

Cell stem cell Pub Date : 2024-08-01 Epub Date: 2024-06-14 DOI:10.1016/j.stem.2024.05.008
Jason S Kirk, Jie Wang, Mark Long, Spencer Rosario, Amanda Tracz, Yibing Ji, Rahul Kumar, Xiaozhuo Liu, Anmbreen Jamroze, Prashant K Singh, Igor Puzanov, Gurkamal Chatta, Qing Cheng, Jiaoti Huang, Jeffrey L Wrana, Jonathan Lovell, Han Yu, Song Liu, Michael M Shen, Tao Liu, Dean G Tang
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Abstract

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.

Abstract Image

单细胞综合分析确定了耐阉割前列腺管腔细胞的表观遗传学基础。
了解前列腺对阉割和雄激素受体信号抑制剂(ARSI)的反应对于提高前列腺癌(PCa)患者的长期生存率至关重要。在这里,我们采用多组学方法对 229,794 个单细胞进行研究,建立了小鼠单细胞参考图谱,用于解释小鼠前列腺生物学和阉割反应。我们的参考图谱完善了单细胞注释并提供了染色质背景,结合小鼠系谱追踪,证明了耐阉割管腔细胞有别于之前存在的尿道近端干细胞/祖细胞。分子通路分析和治疗研究进一步表明,AP1(JUN/FOS)、WNT/β-catenin、FOXQ1、NF-κB 和 JAK/STAT 通路是阉割耐药管腔细胞的主要驱动因素,与人类 PCa 相关。我们的数据集可通过互动门户网站(https://visportal.roswellpark.org/data/tang/)进行浏览,有助于开发针对晚期PCa患者的ARSI联合疗法。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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