Regulation of prostate epithelial basal cell plasticity

Project Summary Prostatitis is a common urinary tract problem for men. Although pathological and epidemiological studies have linked prostatitis to the development of prostate cancer, its molecular mechanism remains unclear. Answering this question will have clinical benefits in prostate cancer prevention and early intervention. It has been proposed that inflammation can induce tissue stem cell expansion, thereby enlarging the cellular pool for oncogenic transformation. In the prostate, epithelial basal cells serve as stem cells during organogenesis and injury repair, but are quiescent in adult homeostasis. Preliminary data in mouse models suggest that prostatitis reactivates adult basal cells to promote basal-to-luminal differentiation, which facilitates the initiation and progression of prostate cancer. The goal of this project is to elucidate the mechanisms regulating basal cell plasticity in prostatitis and apply the knowledge for prostate cancer prevention. Our central hypothesis is that dysregulation of the androgen receptor (AR) and Wnt signaling crosstalk through an increase of Wnt/β-catenin activity and insufficient AR sequestration is a major factor underlying basal cell reactivation in prostatitis. In three specific aims, we will use an integrated approach of mouse genetics, in vivo lineage tracing, prostate organoid culture, ChIP-seq, biochemistry, single cell RNA-seq, and bioinformatics to determine the AR and β-catenin cistromes in basal cells in prostatitis, characterize the inflammatory stromal environment essential for the enhancement of basal Wnt activities, and assess the effectiveness of Wnt inhibition in delaying prostatitis-stimulated cancer. This project will provide novel insights into the mechanistic link between prostatitis and prostate cancer, a long-standing question in the field. The research outcomes will positively impact human health since Wnt signaling is a druggable target and its inhibition is a potentially promising treatment for ameliorating prostatitis-induced cancer progression.