Project 3: Sex-specific differences in the tumor microenvironment alter glioblastoma growth

项目 3：肿瘤微环境中的性别特异性差异改变胶质母细胞瘤的生长

• 批准号: 10023716
• 负责人: Justin D. Lathia
• 金额: $ 37.56万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-14 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10023716
• 关键词: Adhesions; Advanced Malignant Neoplasm; Astrocytes; Attenuated; Biological; Brain; Cell Communication; Cell Maintenance; Cell Proliferation; Cell physiology; Cells; Data; Epigenetic Process; Female; Foundations; Four Core Genotypes; Future; Genetic; Genotype; Glioblastoma; Glioma; Goals; Growth; Human; Immune; Implant; Incidence; Individual; Inflammation; Innate Immune Response; Iron; Knock-out; Knockout Mice; LCN2 gene; Lead; Libido; Malignant Neoplasms; Malignant neoplasm of brain; Mediating; Microglia; Microscopy; Modeling; Molecular; Molecular Target; Mus; Myeloid-derived suppressor cells; Operative Surgical Procedures; Pathway interactions; Patients; Pharmacology; Phenotype; Plant Roots; Population; Precision therapeutics; Proteins; Radiation; Reporting; Resistance; Resolution; Role; Sex Differences; Signal Pathway; Signal Transduction; Testing; Therapeutic; Time; Transplant Recipients; Tumor Cell Invasion; Tumor Suppressor Proteins; Validation; Wild Type Mouse; Work; aggressive therapy; base; brain cell; cancer stem cell; cellular targeting; chemotherapy; conventional therapy; drug development; epidemiology study; experience; genetic signature; genotypic sex; granulocyte; host neoplasm interaction; human tissue; imaging platform; immune activation; in vivo; in vivo imaging; insight; interest; iron metabolism; junctional adhesion molecule; macrophage; male; mouse model; multi-photon; neoplastic; neoplastic cell; novel therapeutics; outcome forecast; personalized medicine; precision medicine; programs; receptor; self-renewal; sex; sexual dimorphism; single-cell RNA sequencing; stem cells; synergism; therapy resistant; tumor; tumor growth; tumor microenvironment; tumor progression; tumorigenesis; tumorigenic; uptake

PROJECT SUMMARY Glioblastoma (GBM) is the most prevalent primary malignant brain tumor and continues to progress despite aggressive therapies including surgery, radiation, and chemotherapy. The interaction between tumor cells and their surrounding microenvironment directly impacts their growth and resistance to conventional therapies. We have had a long-standing interest in the mechanisms responsible for cellular interactions in the context of cancer stem cells (CSCs) and previously identified a pro-tumiogenic function for junctional adhesion molecule- A (JAM-A) in CSC maintenance. To test the function of JAM-A in the tumor microenvironment, we utilized JAM-A knockout mice to assess the growth of syngeneic mouse glioma cells. We found sex-specific differences in survival, with female knockout mice having more aggressive tumors, suggesting that JAM-A functioned as a tumor suppressor in the female microenvironment. Additional assessments revealed an increase in the number and activation status microglia, the native immune cells of the brain, and lipocalin 2 (LCN2) signaling in the female JAM-A knockout mice, highlighting an underlying sex-specific difference in the function of JAM-A in the tumor microenvironment. These findings serve as the basis for this project to further interrogate this newly identified, sex-specific difference in JAM-A in the tumor microenvironment in the context of a larger Program Project application on sex differences in GBM. The translational goal of this project is to conduct mechanistic studies on the sex-specific function of JAM-A in immune cells in the tumor microenvironment. This will be achieved using a combination of genetic mouse models, syngeneic mouse glioma models, and a high-resolution assessments of immune cells in the tumor microenvironment and in vivo imaging platform, with validation in human tissue. We hypothesize that JAM-A functions as a female microenvironment tumor suppressor by reducing microglial and immune activation and LCN2 signaling. Aim 1 will test the hypothesis that JAM-A functions as a tumor suppressor in females via differential microglia activation and tumor-host interactions. Aim 2 will test the hypothesis that LCN2 in the GBM microenvironment enhances tumor cellular iron uptake and can be targeted to attenuate tumor growth and invasion in a sex-specific manner. The long-term goal of this project is to identify the function of JAM-A in the GBM microenvironment and pinpoint specific mechanisms that can be leveraged to reduce GBM growth for sex-specific personalized medicine approaches. This project integrates with Project 1 and Project 2 of this P01 and will be enhanced by the cores. Results from this project will impact Project 1 by providing an opportunity to determine whether cell intrinsic or extrinsic sex differences are the dominant contributor to tumor growth and dispersion and will impact Project 2 by determining how sex-specific immune cell differences can synergize with or neutralize iron metabolism.

项目摘要 胶质母细胞瘤（GBM）是最常见的原发性恶性脑肿瘤，尽管有严重的肿瘤， 包括手术、放疗和化疗在内的积极治疗。肿瘤细胞与 它们周围的微环境直接影响它们的生长和对常规疗法的抵抗力。我们 一直以来，他们都对细胞相互作用的机制感兴趣， 癌症干细胞（CSCs）和先前确定的促肿瘤功能的连接粘附分子- CSC维护中的A（JAM-A）。为了测试JAM-A在肿瘤微环境中的功能，我们使用了 JAM-A敲除小鼠以评估同基因小鼠神经胶质瘤细胞的生长。我们发现了性别特异性 存活率的差异，雌性基因敲除小鼠具有更具侵袭性的肿瘤，这表明JAM-A 在女性微环境中发挥肿瘤抑制因子的作用。其他评估显示， 小胶质细胞、大脑的天然免疫细胞和脂质运载蛋白2的数量和激活状态增加 在雌性JAM-A基因敲除小鼠中的LCN 2信号传导，突出了在LCN信号传导中潜在的性别特异性差异。 JAM-A在肿瘤微环境中的作用这些发现是该项目进一步开展的基础。 在肿瘤微环境中询问这种新发现的性别特异性JAM-A差异， 关于GBM性别差异的大型项目申请。 本项目的翻译目标是对JAM-A的性别特异性功能进行机制研究， 肿瘤微环境中的免疫细胞。这将通过使用基因小鼠的组合来实现 模型，同基因小鼠胶质瘤模型，以及肿瘤中免疫细胞的高分辨率评估 微环境和体内成像平台，并在人体组织中进行验证。我们假设JAM-A 作为女性微环境肿瘤抑制因子通过减少小胶质细胞和免疫 激活和LCN 2信号传导。目的1将检验JAM-A在肿瘤细胞中作为肿瘤抑制因子发挥作用的假设。 女性通过差异小胶质细胞活化和肿瘤宿主相互作用。目标2将检验以下假设： GBM微环境中的LCN 2增强肿瘤细胞铁摄取，并可靶向减弱 肿瘤的生长和侵袭具有性别特异性。本项目的长期目标是确定 JAM-A在GBM微环境中的作用，并指出可以利用的具体机制，以减少 性别特异性个性化医疗方法的GBM增长。该项目与项目1相结合， P01的项目2，并将通过核心进行增强。该项目的结果将通过以下方式影响项目1 提供了一个机会，以确定是否细胞内在或外在的性别差异是占主导地位的， 肿瘤生长和扩散的贡献者，并将通过确定性别特异性免疫如何影响项目2 细胞差异可以协同或中和铁代谢。