PD07-10 STROMAL ANDROGEN RECEPTOR INHIBITS PROSTATE TUMOR PROGRESSION BY RESTRAINING SECRETORY LUMINAL EPITHELIAL CELLS

Abstract

You have accessJournal of UrologyCME1 May 2022PD07-10 STROMAL ANDROGEN RECEPTOR INHIBITS PROSTATE TUMOR PROGRESSION BY RESTRAINING SECRETORY LUMINAL EPITHELIAL CELLS Zhu Wang, Yueli Liu, Jiawen Wang, Corrigan Horton, Joshua Stefanson, and Qing Xie Zhu WangZhu Wang More articles by this author , Yueli LiuYueli Liu More articles by this author , Jiawen WangJiawen Wang More articles by this author , Corrigan HortonCorrigan Horton More articles by this author , Joshua StefansonJoshua Stefanson More articles by this author , and Qing XieQing Xie More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002526.10AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Androgen receptor (AR) is expressed in both the prostate epithelium and stroma, and plays cell-type-specific roles in development and prostate cancer (PCa). While it is well established that stromal AR is required for epithelial cell growth in prostate development, how it affects PCa progression remains unclear. Clinically, lower expression of stromal AR is associated with advanced PCa and worse patient outcome. Yet several renal grafting and mouse model studies reported a role for stromal AR in promoting PCa progression. The discrepancy may be attributed to a negligence of developmental vs adult prostate stages in previous studies. The objective of this study is to clarify the role of stromal AR in PCa using rigorous mouse model designs and investigate its mechanism. METHODS: We deleted stromal AR strictly at adult stage by tamoxifen-inducing the Myh11-CreERT2 line in the Hi-Myc and the hormonal carcinogenesis T+E2 mouse models (named strAR-Myc and strAR-T+E, respectively, as experimental groups). Myc and T+E mice with wildtype stroma served as controls. We assessed tumor histology for both models through time by H&E and assigned a score for each sample in a double-blind setting. Experimental and control groups were compared using two-sided t-test. We next performed single cell RNA-seq (scRNA-seq) of T+E and strAR-T+E samples to determine which cell type was altered and used gene set enrichment analysis (GSEA) to determine the affected molecular pathway. RESULTS: Fig A shows that stromal AR loss consistently resulted in higher H&E scores (more aggressive) in both models. UMAP in Fig B shows that secretory luminal cells were particularly altered by stromal AR loss. GSEA analyses of multiple datasets revealed that the PI3K pathway was potentiated in a subset luminal cells of the strAR-T+E tumor. CONCLUSIONS: Stromal AR normally inhibits PCa progression by restraining the PI3K activity within luminal tumor cells. This implies that conventional androgen deprivation therapy may have unintended negative consequence due to stromal AR loss. Source of Funding: NIH R01GM116872 © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e102 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Zhu Wang More articles by this author Yueli Liu More articles by this author Jiawen Wang More articles by this author Corrigan Horton More articles by this author Joshua Stefanson More articles by this author Qing Xie More articles by this author Expand All Advertisement PDF DownloadLoading ...