Cellular cartography reveals mouse prostate organization and determinants of castration resistance [multiome]

Inadequate response to Androgen Deprivation Therapy (ADT) frequently arises in Prostate Cancer (PCa) via unclear cellular mechanisms and drives aggressive forms of the disease. Here, we integrated single-cell RNA sequencing, single-cell multiomics and spatial transcriptomics to reveal the transcriptional, epigenetic and spatial basis of cell identity and cell-specific castration response in mouse prostates, and used this reference along with meta-analysis to identify determinants of ADT-response and castration resistance in human PCa. We found that that the mouse prostate contains lobe-specific luminal epithelial cell types (LEs), as driven by unique gene regulatory modules, and anatomically-defined androgen responsive transcriptional programs, which together indicate developmental divergence. Androgen recalcitrant stem-like epithelia that bear semblance to Club and Hillock cells of the human prostate were enriched in the urethra and Ventral Prostate (VP), but rarely present in other lobes. Strikingly, the VP contained two additional LEs, Pbsn-positive and Spink1-positive (enriched in SPOP mutant PCa) androgen responsive cells, which effectively mapped to human LEs and potentially denote cell types that drive distinct PCa subtypes. Castration reorganized LE transcriptomes, with castration resistant LEs activating stress responsive (e.g. Nfe2l2) and stemness (e.g. Klf6) programs. Tumor cells of ADT-treated and Castration Resistant PCa patients were enriched for these castration programs, suggesting their role in driving the emergence and sustenance of castration resistance. Overall, our cellular cartography effort culminates in a comprehensive atlas of the mouse prostate, highlights the potential for lobe-specific PCa modeling in mice and identifies potential therapeutic targets that inhibit castration resistance.