Elucidating oncogenic effects of androgen signaling in prostate tumorigenesis through aberrant activation of IGF1 and WNT signaling pathways [scRNA-Seq 2]

Although a promotional role of the androgen receptor (AR) has been implicated in prostate tumorigenesis, the underlying mechanisms by which the AR, as a steroid-hormone receptor, induces prostatic oncogenesis still remain unknown. Conditional expression of the human AR transgene (hARtg) through Osr1 (old skipped related1) driven-Cre develops high-grade prostatic intraepithelial neoplasia (HGPIN) and adenocarcinomas in mice. Single-cell transcriptomic and genetic tracing analyses implicate the prostatic progenitor properties of prostatic Osr1-expressing cells through prostate development. Conditional expression of hARtg in Osr1-expressing basal epithelial cells elevates IGF1 signaling and initiates prostate oncogenesis and PIN formation. Aberrant IGF1 signaling further cumulates Wnt/b-catenin activation in atypical PIN cells to promote tumor development. Specific inhibition of Wnt signaling pathways significantly represses the growth of hARtg-positive prostate tumor cells in ex-vivo and xenograft models. These data elucidate a new and dynamic regulatory loop initiated by aberrant AR signaling altering IGF1 and Wnt signaling pathways in prostate oncogenesis and tumor development. Overall design: Two sequencing datasets were analyzed containing prostatic intraepithelial neoplasia (PIN) and adenocarcinoma (PCa) tissues