Interstitial fibroblasts drive prostate branching morphogenesis

Interstitial fibroblasts drive prostate branching morphogenesis Douglas W. Strand, PI Chad Vezina, Co-I UT Southwestern Medical Center, Dallas, TX Summary The paracrine factors that drive prostate development and disease are still unknown. We recently discovered a population of interstitial fibroblasts that surround the prostatic urethra of the normal prostate and are sparse in the transition zone. We showed that the characteristic nodules that form in human benign prostatic hyperplasia (BPH) are an expansion of interstitial fibroblasts in the transition zone. Key preliminary spatial transcriptomic analysis of interstitial fibroblasts inside BPH nodules revealed the enrichment of mitogens and morphogens that are normally only expressed during organogenesis. These data represent a breakthrough in our understanding of stromal-epithelial interactions in human BPH and could help solve the long-held hypothesis that BPH is a reawakening of the embryonic signaling that induces prostate development. We will test the hypothesis that paracrine signaling from interstitial fibroblasts drives prostate branching morphogenesis in development and disease with three critical lines of inquiry: 1) spatial transcriptomics analysis of interstitial fibroblasts in human prostate development and BPH; 2) mechanistic analysis of paracrine morphogens and mitogens on adult prostate epithelial proliferation and branching ex vivo; and 3) in vivo analysis of autocrine regulation of prostate epithelial proliferation by the receptors of interstitial fibroblast ligands. Successful completion of our aims will establish a new mechanism of prostate growth that is actionable in clinical trials. Relevance Establishing the paracrine factors responsible for prostate growth holds great promise for identifying novel approaches to medical therapy for the reversal or prevention of hyperplasia.