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

项目总结 胶质母细胞瘤(GBM)是最常见的原发恶性脑肿瘤，尽管如此，它仍在继续发展 积极的治疗方法，包括手术、放疗和化疗。肿瘤细胞与肿瘤细胞间的相互作用 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 长期以来一直对负责细胞相互作用的机制感兴趣 癌症干细胞(CSCs)，此前发现了连接黏附分子的促肿瘤功能- A(JAM-A)在CSC维护中。为了测试JAM-A在肿瘤微环境中的功能，我们利用 JAM-A基因敲除小鼠评估同基因小鼠胶质瘤细胞的生长情况。我们发现了特定性别的 存活率的差异，雌性基因敲除小鼠的肿瘤侵袭性更强，这表明JAM-A 在女性的微环境中起到肿瘤抑制的作用。其他评估显示 增加小胶质细胞的数量和激活状态，小胶质细胞是大脑的天然免疫细胞，以及Lipocalin 2 (Lcn2)在雌性JAM-A基因敲除小鼠中的信号，突出了潜在的性别差异 JAM-A在肿瘤微环境中的作用这些发现是本项目进一步发展的基础 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性别差异的一个更大的项目项目申请。 该项目的翻译目标是对JAM-A的性别特异性功能进行机械性研究 肿瘤微环境中的免疫细胞。这将通过使用遗传老鼠的组合来实现 模型、同基因小鼠胶质瘤模型和肿瘤中免疫细胞的高分辨率评估 微环境和活体成像平台，在人体组织中进行验证。我们假设Jam-A 通过减少小胶质细胞和免疫功能发挥女性微环境肿瘤抑制因子的作用 激活和Lcn2信号。目标1将检验JAM-A作为肿瘤抑制因子的假设 雌性通过不同的小胶质细胞激活和肿瘤与宿主的相互作用。目标2将检验这一假设 GBM微环境中的Lcn2可增强肿瘤细胞的铁摄取，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 对GBM微环境中的JAM-A进行评估，并找出可以用来减少 针对特定性别的个性化医疗方法的GBM增长。该项目与项目1和 这是P01项目2的一部分，并将通过核心得到加强。此项目的结果将通过以下方式影响项目1 提供了一个机会来确定细胞的内在或外在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 细胞差异可以协同铁代谢或中和铁代谢。

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.