Abstract 1579: Increased stromal-oriented MAOB expression associated with poor clinical outcomes promotes prostate cancer progression

Abstract

Abstract Background. Stromal fibroblasts, the predominant cell type within the tumor microenvironment, plays a critical regulatory role in prostate cancer (PC) by engaging in stromal-epithelial interactions to dictate cancer initiation, growth, and progression. Monoamine oxidase B (MAOB) catalyzes oxidative deamination of biogenic and dietary monoamines and generates hydrogen peroxide as a by-product, which can predispose stromal cells to a reactive, cancer-promoting state with elevated production of extracellular matrix molecules, growth factors, cytokines, and chemokines. This study investigated the clinical relevance and previously unrecognized function of stromal MAOB in PC. Methods. The stromal MAOB expression levels were determined in PC clinical specimens by immunohistochemistry and in publicly available multi-omics cancer datasets, which were associated with different clinical parameters. The human prostatic stromal fibroblast PrSC cells engineered for stable overexpression or knockdown of MAOB were co-cultured with a panel of human PC cells in 2-D or 3-D fashion, followed by examination of cancer cell behavior by cell proliferation, migration, and invasion assays. MAOB-knockdown PrSC cells were co-inoculated with luciferase-tagged PC cells as subrenal tissue recombinant xenografts into mice for assessment of MAOB’s impact on tumor growth by bioluminescence imaging. Results. MAOB expression was induced in the stroma associated with primary PC compared to normal prostatic tissues of clinical samples, which was corroborated by the same MAOB expression trend in three matched pairs of patient-derived fibroblasts. Following the analysis of three independent clinical cohorts, increased stromal MAOB levels were shown to be correlated with higher Gleason scores, castration resistance, survival, and appearance of neuroendocrine differentiation as evidenced by CHGA expression in the adjacent epithelia. Co-culturing MAOB-overexpressing PrSC cells with several human PC cell lines (C4-2, PC-3, DU145 and C4-2BENZR) accelerated cancer cell proliferation, migration, and invasion. Conversely, these cancer cell phenotypes were suppressed in the presence of MAOB-knockdown PrSC cells. Additionally, C4-2 tumor xenografts when co-inoculated with MAOB-knockdown PrSC grew to a substantially smaller size in mice, which was paralleled by reduced Ki-67 index and reactive stromal marker αSMA expression in the tumor and stromal compartments respectively, compared to controls. Conclusion. Our results suggest that the elevated MAOB expression in PC stromal cells is associated with poor clinical outcomes and further contributes to adjacent PC growth, which provides new insights into understanding the stromal support of PC pathogenesis and progression. Funding provided by the NIH/NCI grant R01CA258634 and WSU CPPS startup fund (to B.W). Citation Format: Tainjie Pu, Jing Wang, Chia-Hui Chen, Tzu-Ping Lin, Boyang Wu. Increased stromal-oriented MAOB expression associated with poor clinical outcomes promotes prostate cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1579.