Deciphering Mechanisms of Tumor-Stromal Interactions in Prostate Cancer

Project Summary/Abstract Prostate cancer (PC) affects 1 in 9 men and causes nearly 30,000 yearly deaths in the United States. Understanding the PC tumor microenvironment (TME) is essential for optimizing cancer prevention and care. Unlike highly mutable tumor cells, non-cancerous stromal cells in the TME, consisting primarily of cancer associated fibroblasts (CAFs), are a genetically stable and attractive therapeutic target in PC, with reduced risk of acquired resistance from genetic changes. Our long-term goals are to elucidate the molecular mechanisms governing stromal support of PC growth and progression, and identify potential druggable therapeutic targets in the stromal compartment to disrupt tumor-stromal interactions. We recently found that monoamine oxidase B (MAOB), a mitochondrial oxidative enzyme responsible for degrading monoamine neurotransmitters and dietary amines, is highly induced in PC stromal cells compared to normal prostate stromal cells in patient samples, PTEN-knockout (KO) transgenic mice and primary cultures of patient-derived CAFs. Stromal MAOB expression further increases during disease progression toward castration resistance and neuroendocrine differentiation, compared to hormone-naïve disease. Our epidemiological studies revealed that men taking MAOB inhibitors for neurological disorders such as depression tend to have a lower incidence of PC. Functional studies showed that MAOB ablation in prostate stromal cells profoundly suppressed co-cultured PC cell proliferation/invasion and co-inoculated xenograft/allograft prostate tumor growth in mice. Mechanistically, gene profiling, bioinformatics and phenotypic analyses indicate that stromal MAOB heightens cellular reactive oxygen species (ROS) levels and chemotaxis/chemokine secretion, particularly CXCL13. Based on these new findings, we hypothesize that the elevated expression of MAOB in PC stromal cells promotes adjacent epithelial PC development and progression, and that targeting MAOB and its downstream effectors in stromal cells is an effective strategy to treat PC. In Aim 1, we will determine the functional role of MAOB in stromal activation and its contribution to tumor growth and progression in tissue recombinant xenograft immunocompromised mice and MAOB-KO immunocompetent mice. In Aim 2, we will investigate the molecular mechanism by which MAOB mediates tumor-stromal communication in PC, specifically dissecting how Twist1 cooperates with TGFβ1/Smad3/4 by ROS to activate CXCL13 and how the CXCL13/CXCR5 paracrine axis impacts PC cell behaviors and associated novel signaling pathways in the context of MAOB. We will also establish the relevance of our mechanistic findings in a large collection of human PC samples and assess correlations with disease status. In Aim 3, we will evaluate the efficacy of MAOB inhibitors for treating PC, including castration-resistant PC, in xenograft and syngeneic mouse prostate tumor models. These studies have tremendous biological, pathological and clinical implications for the future application of clinical MAOB inhibitors and development of TME-targeted therapies to complement existing tumor cell-centric PC therapies.