A new and non-autonomous role of androgen signaling in prostate tumorigenesis

Project Summary Androgen signaling, mediated through the androgen receptor (AR) and androgens, plays a central role in prostate tumorigenesis. Over the past decades, significant effort has been devoted to determining the intrinsic mechanism underlying AR action in prostate tumor cells. Androgen deprivation therapy (ADT), directly targeting AR-expressing prostate tumor cells fails in most prostate cancer patients who consequently develop castration resistant prostate cancer (CRPC), an incurable disease. Therefore, the role of AR in prostate tumorigenesis needs to be re-evaluated for designing effective therapeutic strategies. A non-autonomous role of androgen signaling pathways in prostate cancer tumorigenesis has been identified recently. Emerging evidence has shown that aberrant AR activation in prostatic stroma promotes prostate epithelial oncogenesis and tumor formation. Moreover, recent studies further demonstrated that prostatic tumor stroma supports androgen independence and hormone refractoriness during prostate cancer progression. However, the underlying mechanisms by which stromal AR facilitates oncogenic transformation of prostate epithelial cells through paracrine interactions between prostatic epithelium and stroma remain largely elusive. Specifically, the cellular properties of the stromal cells that can convey androgen signaling to regulate prostatic epithelial oncogenesis are largely unclear. Recently, we demonstrated a tumor niche role of stromal AR signaling in Gli1-expressing cells in promoting prostate epithelial oncogenesis and tumor development. Single-cell RNA sequencing and other experimental analyses showed robust increased expression of insulin- like growth factor binding protein 3 (IGFBP3) in prostatic stromal AR-null Gli1-lineage cells, which reduces IGF1 secretion, lessens ligand-induced IGF1R activation, and impairs Wnt/β-catenin-induced prostatic epithelial oncogenesis in adjacent basal epithelial cells. These data implicate a new and non-autonomous role of androgen signaling in prostatic Gli1-lineage cells acting as tumor niches to support prostate epithelial tumorigenesis. In this study, we propose a series of rigorous experiments to test our central hypothesis that the non-autonomous AR action in prostatic Shh-responsive Gli1-lineage cells promotes prostate epithelial oncogenesis, tumor initiation, progression, and CRPC development. The proposed studies are expected to break new ground in many aspects regarding stromal androgen signaling in prostate tumorigenesis. Successful completion of the proposed study should lead to the development of new therapeutic strategies for treating advanced prostate cancer.