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

基本信息

批准号：
10653091
负责人：
Justin D. Lathia
金额：
$ 36.17万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-14 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10653091
关键词：
Acceleration Adhesions Advanced Malignant Neoplasm Astrocytes Attenuated Biological Brain Cell Adhesion Cell Communication Cell Maintenance Cell Proliferation Cell physiology Cells Data Endowment Epigenetic Process Female Foundations Four Core Genotypes Future Genetic Genotype Glioblastoma Glioma Goals Growth Human Immune Implant Incidence Individual Inflammation Innate Immune Response Invaded Iron Knock-out Knockout Mice LCN2 gene Macrophage Malignant Neoplasms Malignant neoplasm of brain Mediating Microglia Modeling Molecular Molecular Target Mus Myeloid-derived suppressor cells Neoplasm Metastasis Operative Surgical Procedures Pathway interactions Patients Phenotype Population Precision therapeutics Prognosis Property Protein Secretion Radiation therapy Reporting Resistance Resolution Role Sex Differences Signal Pathway Signal Transduction Testing Therapeutic Time Transplant Recipients Tumor Cell Invasion Tumor Promotion Tumor Suppressor Proteins Validation Wild Type Mouse Work aggressive therapy brain cell cancer stem cell cellular targeting chemotherapy conventional therapy drug development epidemiology study experience genetic signature genotypic sex glial activation granulocyte host neoplasm interaction human tissue imaging platform immune activation in vivo in vivo imaging insight interest iron metabolism junctional adhesion molecule male mouse model multiphoton microscopy neoplastic neoplastic cell novel therapeutics personalized medicine pharmacologic precision medicine programs receptor self-renewal sex sexual dimorphism single-cell RNA sequencing stem cells synergism therapy resistant translational goal tumor tumor growth tumor microenvironment tumor progression tumorigenesis tumorigenic uptake

项目摘要

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.

项目概要胶质母细胞瘤（GBM）是最常见的原发性恶性脑肿瘤，尽管积极的治疗包括手术、放疗和化疗。肿瘤细胞与肿瘤细胞之间的相互作用他们周围的微环境直接影响他们的生长和对传统疗法的抵抗力。我们长期以来对负责细胞相互作用的机制产生了兴趣癌症干细胞（CSC）和先前发现的连接粘附分子的促肿瘤功能 - CSC 维护中的 A (JAM-A)。为了测试 JAM-A 在肿瘤微环境中的功能，我们利用 JAM-A 敲除小鼠用于评估同基因小鼠神经胶质瘤细胞的生长。我们发现性别特异性存活率存在差异，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作用。额外的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雌性 JAM-A 敲除小鼠中的 (LCN2) 信号转导，强调了潜在的性别特异性差异 JAM-A 在肿瘤微环境中的功能。这些发现作为该项目进一步发展的基础探究肿瘤微环境中 JAM-A 新发现的性别特异性差异关于 GBM 性别差异的大型计划项目应用。该项目的转化目标是对 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。这将通过基因小鼠的组合来实现模型、同基因小鼠神经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了验证。我们假设 JAM-A 通过减少小胶质细胞和免疫来发挥女性微环境肿瘤抑制因子的作用激活和 LCN2 信号传导。目标 1 将检验 JAM-A 作为肿瘤抑制因子的假设女性通过差异小胶质细胞激活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LCN2增强肿瘤细胞铁的摄取，并可靶向减弱肿瘤的生长和侵袭具有性别特异性。该项目的长期目标是确定功能 JAM-A 在 GBM 微环境中的作用，并查明可用于减少的具体机制 GBM 生长针对特定性别的个性化医疗方法。该项目与项目 1 集成，这个P01的项目2将由核心增强。该项目的结果将通过以下方式影响项目 1：提供机会确定细胞内在性别差异或外在性别差异是否占主导地位促进肿瘤生长和扩散，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。