# Deciphering Mechanisms of Tumor-Stromal Interactions in Prostate Cancer

> **NIH NIH R01** · WASHINGTON STATE UNIVERSITY · 2021 · $398,952

## Abstract

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, pat...

## Key facts

- **NIH application ID:** 10180084
- **Project number:** 1R01CA258634-01
- **Recipient organization:** WASHINGTON STATE UNIVERSITY
- **Principal Investigator:** Boyang Wu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $398,952
- **Award type:** 1
- **Project period:** 2021-05-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10180084

## Citation

> US National Institutes of Health, RePORTER application 10180084, Deciphering Mechanisms of Tumor-Stromal Interactions in Prostate Cancer (1R01CA258634-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10180084. Licensed CC0.

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