Integrated single-cell analysis defines the epigenetic basis of castration-resistant prostate luminal cells (scATAC-seq)

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. Overall design: Prostates from C57Bl/6 wild type mice were collected from intact, castrate, and testosterone regenerated mice at 12 weeks of age. Mice were castrated for 4 weeks and regenerated for 96 hours with testosterone pellets. Prostates were digested into single cells and analyzed using scRNAseq and scATACseq to understand prostate cell response to castration and regeneration.