Elucidating oncogenic effects of androgen signaling in prostate tumorigenesis through aberrant activation of IGF1 and WNT signaling pathways [scRNA-Seq 1]

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. Three sequencing datasets were analyzed containing E18.5 male UGS and P14 & P35 prostate tissues尽管雄激素受体（androgen receptor, AR）的促瘤作用已被证实与前列腺肿瘤发生密切相关，但其作为类固醇激素受体诱导前列腺致癌的具体分子机制仍未明确。通过Osr1（old skipped related1）驱动的Cre重组酶介导人雄激素受体转基因（human AR transgene, hARtg）的条件性表达，可在小鼠体内诱发高级别前列腺上皮内瘤变（high-grade prostatic intraepithelial neoplasia, HGPIN）与腺癌。单细胞转录组与遗传谱系示踪分析显示，在前列腺发育进程中，表达Osr1的前列腺细胞具备前列腺祖细胞特性。在表达Osr1的前列腺基底上皮细胞中条件性表达hARtg，可激活胰岛素样生长因子1（IGF1）信号通路，进而启动前列腺致癌过程与前列腺上皮内瘤变形成。异常激活的IGF1信号通路会进一步促进非典型前列腺上皮内瘤变细胞中Wnt/β-连环蛋白（Wnt/β-catenin）通路的活化，从而推动肿瘤进展。在体外实验与异种移植模型中，特异性抑制Wnt信号通路可显著抑制hARtg阳性前列腺肿瘤细胞的增殖。本研究共分析了三组测序数据集，样本涵盖孕18.5天的雄性尿生殖窦（E18.5 male UGS）以及出生后第14天、第35天的前列腺组织。