Deciphering Mechanisms of Tumor-Stromal Interactions in Prostate Cancer

破译前列腺癌肿瘤间质相互作用的机制

• 批准号: 10646159
• 负责人: Boyang Wu
• 金额: $ 37.7万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10646159
• 关键词: 3-Dimensional; Ablation; Affect; Allografting; Amines; Androgen Antagonists; Antibodies; BLR1 gene; Binding; Bioinformatics; Biological; CRISPR/Cas technology; CXCL13 gene; Castration; Cell Proliferation; Cells; Cessation of life; Chemotaxis; Clinical; Clinical Trials; Coculture Techniques; Collection; Combined Modality Therapy; Communication; Complement; Complex; Coupled; D Cells; Development; Disease; Disease Progression; Elements; Enzymes; Epithelium; Fibroblasts; Foundations; Future; Gene Expression Profiling; Genes; Genetic Transcription; Goals; Growth; Hormones; Human; Hydrogen Peroxide; Immunocompetent; Immunocompromised Host; Incidence; Inflammatory; Intervention; Invaded; Knock-out; Knowledge; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Mental Depression; Mitochondria; Mitochondrial Proteins; Molecular; Monoamine Oxidase B; Mus; Mutation; Neoplasm Metastasis; Neuroendocrine Prostate Cancer; Neurotransmitters; Oxidative Stress; PTEN gene; Pathologic; Patients; Phenotype; Predisposition; Prostate; Prostate Cancer therapy; Prostatic Neoplasms; Reactive Oxygen Species; Recombinants; Recurrence; Recurrent disease; Recurrent tumor; Resistance; Risk; Role; Sampling; Signal Pathway; Source; Specimen; Stromal Cells; Stromal Neoplasm; Time; Tissues; Transforming Growth Factor beta; Transgenic Mice; United States; Xenograft procedure; cancer care; cancer prevention; carcinogenesis; castration resistant prostate cancer; cell behavior; chemokine; clinical application; clinical translation; cohort; dietary; druggable target; efficacy evaluation; epidemiology study; gene network; genetic resistance; inhibitor; men; monoamine; mouse model; neoplastic cell; nervous system disorder; neuroendocrine differentiation; new therapeutic target; novel; paracrine; pre-clinical; promoter; prostate cancer cell; prostate cancer model; response; success; targeted treatment; therapeutic target; therapy resistant; translational impact; tumor growth; tumor microenvironment; tumor progression; tumorigenic; wound healing

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.

项目摘要/摘要 前列腺癌（PC）影响了9分之一，在美国造成近30，000年的死亡。 了解PC肿瘤微环境（TME）对于优化癌症预防和护理至关重要。 与高度可突变的肿瘤细胞不同，TME中的非癌性基质细胞，主要由癌症组成 相关的成纤维细胞（CAF）是PC中稳定且有吸引力的治疗靶标，风险降低 从遗传变化中获得的抵抗力。我们的长期目标是阐明分子机制 管理PC生长和进展的基质支持，并确定潜在的可药物治疗靶标 在基质隔室中破坏肿瘤 - 块状相互作用。我们最近发现单胺氧化物B （MAOB），一种线粒体氧化酶，负责降解单胺神经递质和 饮食胺在PC基质细胞中高度诱导与患者的正常前列腺基质细胞相比 样品，PTEN-KNOCKOUT（KO）转基因小鼠和患者衍生的CAF的主要培养物。 Stromal Maob 在疾病进展过程中，表达进一步增加 与未经疾病的疾病相比，分化。我们的流行病学研究表明，男人服用 抑郁症等神经系统疾病的MAOB抑制剂往往较低。 功能研究表明，前列腺基质细胞中的MAOB消融深刻抑制了共培养的PC 小鼠的细胞增殖/侵袭和共接种的分类/同种异体移植前列腺肿瘤的生长。机械上， 基因分析，生物信息学和表型分析表明，基质的MAOB增强了细胞反应性 氧水平（ROS）水平和趋化因子分泌，尤其是CXCL13。基于这些新的 调查结果，我们假设MAOB在PC基质细胞中的表达升高会促进相邻 上皮PC的开发和进展，以及针对MAOB及其下游效应 细胞是治疗PC的有效策略。在AIM 1中，我们将确定MAOB在基质中的功能作用 激活及其对组织重组异种移植物的肿瘤生长和进展的贡献 免疫组合的小鼠和MAOB-KO免疫能力小鼠。在AIM 2中，我们将研究分子 MAOB在PC中介导肿瘤 - 层交流的机制，特别剖析了Twist1 与ROS与TGFβ1/SMAD3/4合作以激活CXCL13以及CXCL13/CXCR5旁分泌轴如何 在MAOB的背景下影响PC细胞行为和相关的新型信号通路。我们也会 在大量的人类PC样品中确定我们的机械发现的相关性和评估 与疾病状况相关。在AIM 3中，我们将评估MAOB抑制剂治疗PC的效率， 包括耐castration抗性的PC，在习值和同性小鼠前列腺肿瘤模型中。这些研究 对临床MAOB的未来应用具有巨大的生物学，病理和临床意义 抑制剂和TME靶向疗法的发展以补充现有的以肿瘤细胞为中心的PC疗法。