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: 10653085
• 负责人: JAMES Robert CONNOR
• 金额: $ 35.64万
• 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 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10653085
• 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; 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; Libido; Link; Liver; Macrophage; Malignant Neoplasms; Mediating; Metabolism; Methods; Microglia; Modeling; Molecular; Mus; Outcome; Pathway interactions; Patients; Pharmacologic Substance; Positioning Attribute; Prognosis; Program Research Project Grants; Proteins; Publishing; Qualifying; Regulation; Regulator Genes; Resolution; Sex Differences; Signal Transduction; System; Testing; Therapeutic; Tumor Burden; Woman; biological systems; cancer cell; cell transformation; cell type; dietary; epigenetic regulation; glial activation; human model; immune activation; immunocytochemistry; immunological status; in vivo Model; iron metabolism; junctional adhesion molecule; male; metabolic profile; mouse model; neoplastic cell; programs; receptor binding; sex; sexual dimorphism; single-cell RNA sequencing; synergism; transcriptome sequencing; translational potential; 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.

项目摘要 胶质母细胞瘤（GBM）发病率和生存率的性别差异已得到充分证明，但潜在的 机制还不清楚，导致缺乏治疗策略的临床指导。的 这些性别差异的机制包括细胞内在和系统因素。铁是独一无二的 作为一种关键的细胞内在因子，其全身水平影响肿瘤负荷， 是受性别影响的。铁是调节代谢、基因表达、巨噬细胞/小胶质细胞 功能和整体免疫状态。由于铁在生物系统中至关重要，因此有多种 必须协调稳态细胞和分子途径，包括互补的 肿瘤微环境中不同细胞类型之间的通讯。这种复杂的生物调节 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）是所有细胞铁吸收的关键调节因子，可预测女性的预后，但不能预测女性的预后。 男性GBM患者。此外，外在因素，如脑脊液中铁蛋白的循环水平， 与GBM的不良结局相关，可能与我们的新发现有关，即H-铁蛋白与GBM中的细胞结合 作为性别特异性GBM铁标记的一部分虽然铁状态影响胶质瘤的形成，但铁稳态 途径有具体的基于性别的挑战，如女性贫血的发病率较高，这是根据- 在癌症和这个项目的重点方面受到赞赏。基于多种癌症的已发表数据 根据我们发表的和初步的数据，我们假设，在两种宿主的调节中， 而细胞铁的状况会影响细胞内代谢、基因表达、细胞微环境 相互作用和胶质瘤形成。本提案的目的是描述GBM的铁特征， 然后利用这些数据来询问小鼠和细胞培养模型以确定机制 通过该方法，GBM中的铁信号被细胞内在和环境因素建立和修饰。 我们将通过两个具体目标来检验我们的假设：具体目标1将检验性别特异性的假设。 互补的铁调节信号存在于肿瘤细胞和GBM微环境中; 具体目标2将检验GBM的铁特征显示性二态性的假设， 通过整合细胞内和细胞外铁介导的相互作用驱动肿瘤生长。 这些研究补充了其他P01项目的遗传/表观遗传特征（项目1）和肿瘤 微环境相关炎症状态（项目3）通过桥接细胞内在与细胞外在 通过一种常见机制铁代谢进行致瘤程序。