Deciphering Mechanisms of Tumor-Stromal Interactions in Prostate Cancer

项目概要/摘要 在美国，前列腺癌 (PC) 影响九分之一的男性，每年导致近 30,000 人死亡。 了解 PC 肿瘤微环境 (TME) 对于优化癌症预防和护理至关重要。 与高度可变的肿瘤细胞不同，TME 中的非癌性基质细胞主要由癌症组成 相关成纤维细胞 (CAF) 是 PC 中遗传稳定且有吸引力的治疗靶点，且风险较低 遗传变化带来的获得性抵抗力。我们的长期目标是阐明分子机制 控制 PC 生长和进展的基质支持，并确定潜在的药物治疗靶点 在基质室中破坏肿瘤-基质相互作用。我们最近发现单胺氧化酶B (MAOB)，一种线粒体氧化酶，负责降解单胺神经递质和 与患者正常前列腺基质细胞相比，膳食胺在 PC 基质细胞中被高度诱导 样本、PTEN 敲除 (KO) 转基因小鼠和患者来源的 CAF 的原代培养物。基质MAOB 在疾病进展到去势抵抗和神经内分泌的过程中表达进一步增加 与未经激素治疗的疾病相比，分化。我们的流行病学研究表明，男性服用 用于治疗抑郁症等神经系统疾病的 MAOB 抑制剂往往会降低 PC 的发病率。 功能研究表明，前列腺基质细胞中的 MAOB 消融可显着抑制共培养的 PC 小鼠中的细胞增殖/侵袭和共同接种的异种移植/同种异体移植前列腺肿瘤生长。从机械上来说， 基因分析、生物信息学和表型分析表明基质 MAOB 增强细胞反应性 氧 (ROS) 水平和趋化性/趋化因子分泌，特别是 CXCL13。基于这些新 结果，我们假设 PC 基质细胞中 MAOB 的表达升高会促进邻近的 上皮 PC 的发育和进展，以及靶向基质中 MAOB 及其下游效应子的研究 细胞疗法是治疗 PC 的有效策略。在目标 1 中，我们将确定 MAOB 在基质中的功能作用 组织重组异种移植物中的激活及其对肿瘤生长和进展的贡献 免疫功能低下的小鼠和 MAOB-KO 免疫功能正常的小鼠。在目标 2 中，我们将研究分子 MAOB介导PC中肿瘤间质通讯的机制，具体剖析了Twist1如何 ROS通过ROS协同TGFβ1/Smad3/4激活CXCL13以及CXCL13/CXCR5旁分泌轴如何 影响 MAOB 背景下 PC 细胞的行为和相关的新型信号通路。我们还将 建立我们在大量人类 PC 样本中的机制发现的相关性并评估 与疾病状态的相关性。在目标 3 中，我们将评估 MAOB 抑制剂治疗 PC 的功效， 包括异种移植和同基因小鼠前列腺肿瘤模型中的去势抵抗性 PC。这些研究 对于 MAOB 的未来临床应用具有巨大的生物学、病理学和临床意义 抑制剂和 TME 靶向疗法的开发，以补充现有的以肿瘤细胞为中心的 PC 疗法。

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.