PD02-07 ALTERNATE ANDROGEN-INDEPENDENT PATHWAYS FOR PROSTATE GROWTH IN THE ABSENCE OF SRD5A2

Abstract

You have accessJournal of UrologyCME1 Apr 2023PD02-07 ALTERNATE ANDROGEN-INDEPENDENT PATHWAYS FOR PROSTATE GROWTH IN THE ABSENCE OF SRD5A2 Christina Sharkey, Xingbo Long, Ra'ad Al-Faouri, Aria F. Olumi, and Zongwei Wang Christina SharkeyChristina Sharkey More articles by this author , Xingbo LongXingbo Long More articles by this author , Ra'ad Al-FaouriRa'ad Al-Faouri More articles by this author , Aria F. OlumiAria F. Olumi More articles by this author , and Zongwei WangZongwei Wang More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003219.07AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Benign prostatic hyperplasia (BPH) is a heterogeneous disease that results from the nonmalignant proliferation of both the prostate epithelial and stromal compartments. Steroid 5α reductase 2 (SRD5A2) is the predominant enzyme responsible for prostatic development and growth. Despite the introduction of steroid 5α-reductase inhibitors (5ARI) for benign prostatic hyperplasia (BPH), the progression of LUTS is only slowed by 34% with 5ARI-response. Therefore, we hypothesize that there are alternative pathways driving prostate growth and development when SRD5A2 is absent. To address this question we generated SRD5A2 null (Srd5a2-/-) mouse model and demonstrated that luminal cells with lineage signature and progenitor signature diminished, whereas luminal cells with estrogen response genetic signature stably survived when SRD5A2 is absent. Here we further aim to identify whether the cell-cell interactions between stromal cells and luminal cells with WNT5A are the critical modulators in absence of SRD5A2. METHODS: Single cell RNA sequencing (scRNA seq) and bulk RNA seq was performed with prostate tissues from Srd5a2-/- and Srd5a2+/- littermate control mice. Unbiased scRNA seq with 10x genomics platform, followed by unsupervised clustering, was utilized to generate cell clusters based on differentially expressed (DE) gene profiles. The heterotypic cell-cell communication was analyzed using CellphoneDB2. Identified ligand-receptor pairs were validated by qPCR in BHPrS1 human prostatic stromal cell line and human prostatic tissues with BPH. RNAscope was performed to identify the transcription expression of target genes. RESULTS: The expression of SRD5A2 was exclusively identified in fibroblasts and myofibroblasts. The absence of SRD5A2 induced the increase of stromal cells (11.3% vs. 18.0%) but decrease of luminal cells (53.2% vs. 31.8%). Analysis of ligand-receptor pairs indicated that stromal cells were the most prolific interactors, and myofibroblasts were the most "outbound" cells. Meanwhile, in Srd5a2-/- mice the fibroblasts had the most significantly increased weighted value (366 vs. 493), and LE1, one subset of luminal cells had most significantly decreased weighted value (205 vs. 96). Myofibroblast and muscle system processes were most significantly upregulated in Srd5a2-/- mice as assessed by bulk RNA-seq analysis. Nine highly significant interactions were identified which regulate stromal–luminal cell communication, including WNT5A/PTPRK, TGFB2/TGFBR1, and (NRP1, NRP2, FLT1)/VEGFA. RNAscope data showed a significant upregulation of WNT5A in the anterior prostate of Srd5a2-/- mice (p<0.0001). CONCLUSIONS: Our data suggest that the heterotypic cell-cell communication is substantially changed in the absence of SRD5A2. The stroma-niched signaling, particularly WNT5A and WNT signaling pathway might serve as a therapeutic target for managing BPH patients who lack SRD5A2 expression and may be unresponsive to 5ARI therapies. Source of Funding: NIH/R01 DK124502 © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e71 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Christina Sharkey More articles by this author Xingbo Long More articles by this author Ra'ad Al-Faouri More articles by this author Aria F. Olumi More articles by this author Zongwei Wang More articles by this author Expand All Advertisement PDF downloadLoading ...