Project 2: Sexual Dimorphism of Iron Metabolism in GBM

项目2：GBM铁代谢的性别二态性

• 批准号: 10023715
• 负责人: JAMES Robert CONNOR
• 金额: $ 37.95万
• 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/10023715
• 关键词: Anemia; Astrocytes; Binding; Biological; Biological Availability; Biological Process; Breast; Cancer cell line; Cell Culture Techniques; Cell Proliferation; Cells; Cerebrospinal Fluid; Clinical; Communication; Complement; Complex; Data; Diet; Environmental Risk Factor; Epigenetic Process; Female; Ferritin; Gene Expression; Genetic; Glioblastoma; Glioma; Gliomagenesis; Goals; Growth; H ferritin; Human; Immunosuppression; Incidence; Inflammation; Intrinsic factor; Iron; Kidney; Knock-out; LCN2 gene; Link; Liver; Malignant Neoplasms; Mediating; Metabolism; Methods; Microglia; Modeling; Molecular; Mus; Outcome; Pathway interactions; Patients; Pharmacologic Substance; Positioning Attribute; Program Research Project Grants; Proteins; Publishing; Regulation; Regulator Genes; Resolution; Sex Differences; Signal Transduction; System; Testing; Therapeutic; Tumor Burden; Woman; base; biological systems; cancer cell; cell type; epigenetic regulation; human model; immune activation; immunocytochemistry; immunological status; in vivo Model; iron metabolism; junctional adhesion molecule; macrophage; male; metabolic profile; mouse model; neoplastic cell; outcome forecast; programs; receptor binding; sex; sexual dimorphism; single-cell RNA sequencing; synergism; transcriptome sequencing; tumor; tumor growth; tumor microenvironment; tumorigenic; uptake

PROJECT SUMMARY Sex differences in glioblastoma (GBM) incidence and survival are well documented but the underlying mechanisms are not well understood, resulting in lack of clinical guidance for therapeutic strategies. The proposed mechanisms for these sex differences include cell intrinsic and systemic factors. Iron is uniquely positioned as a critical cell intrinsic factor whose systemic levels impact tumor burden and whose bioavailability is influenced by sex. Iron is required for the regulation of metabolism, gene expression, macrophage/microglial function, and global immune status. Due to the critical importance of iron in biological systems, there are multiple homeostatic cell and molecular pathways that must be coordinated, which include complementary communication among different cell types in the tumor microenvironment. This complex biological regulatory system is collectively defined as the tumor iron signature. We observed that expression of the iron homeostatic regulator gene (HFE), which is a key regulator of iron uptake by all cells, predicts prognosis in female but not male GBM patients. In addition, extrinsic factors such as circulating levels of ferritin in the cerebrospinal fluid are associated with poor outcomes in GBM, likely related to our new finding that H-ferritin binds to cells in the GBM as part of a sex-specific GBM iron signature. While the iron status influences gliomagenesis, iron homeostatic pathways have specific sex-based challenges, such as higher incidence of anemia in women, that are under- appreciated in the context of cancer and the focus of this project. Based on published data in multiple cancers and our published and preliminary data, we hypothesize that sex differences in the regulation of both host and cellular iron status will impact cell-intrinsic metabolism, gene expression, cell:microenvironment interactions and gliomagenesis. The objective of this proposal is to characterize the iron signature of GBM in humans and then to leverage these data to interrogate mouse and cell culture models to identify the mechanisms by which the iron signature in the GBM is established and modified by cell intrinsic and environmental factors. We will test our hypothesis through two specific aims: Specific Aim 1 will test the hypothesis that sex-specific complementary iron regulation signatures are present in tumor cells and the GBM microenvironment; Specific Aim 2 will test the hypothesis that the iron signature of GBM displays sexual dimorphism and drives tumor growth through integration of cell-intrinsic and cell-extrinsic iron-mediated interactions. These studies complement the other P01 projects on genetic/epigenetic features (Project 1) and tumor microenvironment associated inflammation states (Project 3) by bridging cell intrinsic versus cell extrinsic tumorigenic programs through a common mechanism, iron metabolism.

项目总结 胶质母细胞瘤(GBM)发病率和存活率的性别差异已有很好的文献记载，但潜在的 发病机制尚不清楚，导致缺乏治疗策略的临床指导。这个 这些性别差异的机制包括细胞内的和系统的因素。铁是独一无二的 被定位为关键细胞内在因子，其全身水平影响肿瘤负荷，其生物利用度 会受到性别的影响。铁是调节新陈代谢、基因表达、巨噬细胞/小胶质细胞所必需的 功能和全球免疫状态。由于铁在生物系统中的关键重要性，有多种 必须协调的动态平衡细胞和分子通路，包括互补的 肿瘤微环境中不同细胞类型之间的通讯。这种复杂的生物调控 系统统称为肿瘤铁信号。我们观察到铁稳态的表达 调节基因(HFE)是所有细胞铁摄取的关键调节因子，它可以预测女性的预后，但不能 男性基底膜患者。此外，外在因素，如脑脊液中铁蛋白的循环水平 与GBM预后不良有关，可能与我们的新发现H-铁蛋白与GBM中的细胞结合有关 作为特定性别的GBM铁签名的一部分。虽然铁的状态会影响神经胶质瘤的形成，但铁的稳态 路径具有特定的基于性别的挑战，例如女性贫血的发病率较高，而这些贫血的发病率低于 在癌症的背景下和本项目的重点中受到赞赏。基于已发表的多种癌症的数据 以及我们公布的和初步的数据，我们假设性别差异对两种宿主的调节 细胞铁状态会影响细胞内的代谢、基因表达、细胞微环境 相互作用与神经胶质瘤的发生。这项建议的目标是表征GBM的铁签名在 然后利用这些数据来询问小鼠和细胞培养模型以确定其机制 通过它，细胞固有的和环境因素建立和修改了基底膜中的铁特征。 我们将通过两个特定目标来测试我们的假设：特定目标1将测试特定性别的假设 在肿瘤细胞和基底膜微环境中存在互补的铁调节信号； 《特定目标2》将检验这样一种假设，即GBM的铁签名表现出性别二型性和 通过整合细胞内的和细胞外的铁介导的相互作用来推动肿瘤的生长。 这些研究补充了关于遗传/表观遗传特征(项目1)和肿瘤的其他P01项目 微环境相关的炎症状态(项目3)通过连接细胞内在和外在细胞 通过一种共同的机制--铁代谢--进行肿瘤形成。