LAUSR

Prostate cancer is the second most common cancer in men worldwide. The current treatment targeting androgen receptor (AR) expressing cells, androgen deprivation therapy (ADT), eventually fails in most prostate cancer patients who consequently develop castration resistant prostate cancer, an incurable disease. Although significant effort has been devoted to understanding the promotional role of AR action in prostate tumor cells, there is an urgent need to define the specific role of stromal AR in prostate tumorigenesis and needs to be evaluated for designing effective therapy.We directly examined AR in stromal Shh responsive Gli1 lineage cells in prostate oncogenesis and tumor development utilizing in vivo tissue recombination and novel genetically engineered mouse models. AR loss in stromal Gli1 lineage cells reduces prostate epithelial oncogenesis in xenograft models, combining transformed UGE by expression of stabilized β catenin with AR deficient or control UGM. A Myc induced prostatic epithelial tumor mouse model was combined with conditional deletion of AR in Gli1 lineage cells during prepubescent and adult age which showed significant impairment of prostate tumor development. Single cell RNA sequencing revealed a robust increased expression of insulin like growth factor binding protein 3 (IGFBP3) in AR deleted stromal Gli1 lineage cells. Interestingly although no gene manipulation occurred in the epithelium, basal epithelial cells showed reduced IGF1 induced Wnt signaling, due to the increased IGFBP3 expression. Through chromatin immunoprecipitation qPCR, we examined how deletion of AR in Gli1 lineage cells increases IGFBP3 expression. Stromal AR deletion directly alleviates the suppression of Sp1 regulating transcription of IGFBP3, leading to inhibition of oncogenic growth of tumor epithelium in a paracrine manner. To uncover the mechanism for stromal AR in Gli1 lineage as a tumor niche, we used organoid culture systems. In prostatic epithelial organoid cultures, addition of IGFBP3 or conditional media from AR deleted stromal cells blocked tumor cell growth. Overall, the data implicate the novel and specific role of stromal AR in Gli1 lineage cells as a tumor niche to support prostate epithelial tumorigenesis. Dysregulation of stromal AR on IGFBP3 IGF1 signaling suggest an underlying mechanism for hormone refractoriness through the IGF axes. Cotargeting reciprocal interactions of AR and IGF1 pathways between epithelial tumor cells and surrounding tumor niches may improve clinical outcomes for treating advanced prostate cancer. Therefore, given the importance of sex hormone, hedgehog, and IGF1 signaling pathways in human development and tumorigenesis raises new and relevant questions underlying androgen, Shh, and IGF regulated tumor cell niches in tumor initiation and progression. Citation Format: Alex Hiroto, Won Kyung Kim, Christian H. Nenninger, Alyssa J. Buckley, Zijie Sun. Stromal androgen signaling acts as tumor niches to drive prostatic basal epithelial progenitor initiated oncogenesis through IGFBP3 mediated IGF1 induced Wnt activation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2371.