biostudies-literatureKirk JSRoswell Park Alliance FoundationRoswell Park Comprehensive Cancer CenterU.S. Department of DefenseNCI NIH HHSNational Institutes of HealthProstate Cancer Foundation1203-1221.e7https://www.ebi.ac.uk/biostudies/studies/S-EPMC11297676biostudies-literatureUnknown31(8)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 Cell stem cellIntegrated single-cell analysis defines the epigenetic basis of castration-resistant prostate luminal cells.PMC11297676P30CA016056R01CA240290R01 CA240290R21CA237939R01 CA237027R01 CA238005R01CA237027PC220137R01CA238005P30 CA016056PC220273U24 CA274159R21 CA237939R21CA218635R21 CA218635Jamroze ATracz ASingh PKWrana JLKirk JSHuang JLong MLiu SLiu TWang JKumar RYu HLiu XTang DGCheng QLovell JRosario SChatta GJi YShen MMPuzanov IfalseIntegrated single-cell analysis defines the epigenetic basis of castration-resistant prostate luminal cells.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 2024-01-01T00:00:00Z2024 Aug2026-07-15T14:27:19.45Z2025-08-18T09:54:23.584ZS-EPMC112976763887877510.1016/j.stem.2024.05.008