Recent advances in single-cell
RNA-sequencing (
scRNA-seq) technology have facilitated studies of cell states and plasticity in tissue maintenance and
cancer, including in the prostate. Here we present meta-analyses of multiple new and published
scRNA-seq datasets to establish reference cell type classifications for the normal mouse and human prostate. Our analyses demonstrate transcriptomic similarities between epithelial cell states in the normal prostate, in the regressed prostate after
androgen-deprivation, and in primary prostate
tumors. During regression in the mouse prostate, all epithelial cells shift their expression profiles towards a proximal periurethral (PrU) state, demonstrating an
androgen-dependent plasticity that is restored to normal during
androgen restoration and regeneration. In the human prostate, we find progressive rewiring of transcriptional programs across epithelial cell types in benign prostate
hyperplasia and treatment-naïve
prostate cancer. Notably, we detect copy number variants predominantly within
Luminal Acinar cells in prostate
tumors, suggesting a bias in their cell type of origin, as well as a larger field of transcriptomic alterations in non-
tumor cells. Finally, we observe that
Luminal Acinar
tumor cells in treatment-naïve
prostate cancer display heterogeneous
androgen receptor (AR) signaling activity, including a split between high-AR and low-AR profiles with similarity to PrU-like states. Taken together, our analyses of cellular heterogeneity and plasticity provide important translational insights into the origin and treatment response of
prostate cancer.