Christin, J. R. | Search bioRxiv

bioRxiv2025

Dual pathway regulation of castration response and ferroptosis in the prostate epithelium

Understanding how sex hormones maintain tissue integrity--and how their disruption can promote cancer--is a central question in biology. In the prostate, androgen signaling is crucial for development, homeostasis, and cancer, yet the molecular mechanisms underlying tissue regression after androgen-deprivation have remained unknown. Here we show that castration induces epithelial regression via ferroptosis in the normal mouse and human prostate, as well as in prostate tumors. Using in vivo analyses in genetically-engineered mice, supported by validation in human organotypic cultures, we demonstrate that androgen receptor (AR) signaling controls castration response through two distinct pathways: an intrinsic luminal epithelial pathway regulated by the prostate-specific transcription factor NKX3.1, and an extrinsic stromal signal mediated by the secreted factor pleiotrophin (PTN). Together, these AR signaling pathways coordinately regulate biosynthesis of monounsaturated fatty acid (MUFA) phospholipids and GPX4 expression to suppress prostate epithelial ferroptosis. Our findings reveal a sex hormone-regulated ferroptotic program that governs tissue homeostasis and suggest that ferroptosis induction could represent a new therapeutic strategy for prostate cancer.

developmental biology↗

bioRxiv2024

Meta-analyses of mouse and human prostate single-cell transcriptomes reveal widespread epithelial plasticity in tissue regression, regeneration, and cancer

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-naive 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-naive 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.

cancer biology↗