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: 10263182
• 负责人: JAMES Robert CONNOR
• 金额: $ 16.33万
• 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/10263182
• 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; Link; Liver; Malignant Neoplasms; Mediating; Metabolism; Methods; Microglia; Modeling; Molecular; Mus; Outcome; Pathway interactions; Patients; Pharmacologic Substance; Positioning Attribute; Prognosis; 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; dietary; 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; 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.

项目摘要 胶质母细胞瘤（GBM）发病率和生存的性别差异已得到充分记录，但基础 机制尚不清楚，导致缺乏治疗策略的临床指导。这 这些性别差异的拟议机制包括细胞内在和全身因素。铁是独特的 定位为关键细胞内在因素，其全身水平会影响肿瘤负担，并且其生物利用度 受性影响。铁是代谢，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重要性至关重要，因此有多个 必须协调的稳态细胞和分子途径，包括互补 肿瘤微环境中不同细胞类型之间的通信。这个复杂的生物调节 系统统称为肿瘤铁签名。我们观察到铁稳态的表达 调节剂基因（HFE）是所有细胞对铁吸收的关键调节剂，可预测女性的预后，但不能预测 男性GBM患者。此外，外部因素，例如脑脊液中的铁蛋白循环水平是 与GBM中的结果不佳有关，可能与我们的新发现H-铁蛋白与GBM中的细胞结合 作为性别特定的GBM铁签名的一部分。铁状态影响胶质作用，铁稳态 途径具有特定的基于性别的挑战，例如女性贫血的较高发病率，这些挑战较高 在癌症和该项目的重点的背景下受到赞赏。基于多种癌症中发布的数据 以及我们已发布和初步数据，我们假设两个主机的性别差异 细胞铁的状态和细胞中的状态将影响细胞内代谢，基因表达，细胞：微环境 相互作用和神经胶质作用。该提议的目的是表征GBM的铁特征 人类，然后利用这些数据来询问小鼠和细胞培养模型以识别机制 通过该细胞固有和环境因素建立和修改GBM中的铁特征。 我们将通过两个具体目标检验我们的假设：特定目标1将检验以下假设。 肿瘤细胞和GBM微环境中存在互补的铁调节特征。 具体目标2将检验以下假设：GBM的铁签名显示性二态性和 通过整合细胞中性和细胞 - 超支铁介导的相互作用来驱动肿瘤生长。 这些研究补充了有关遗传/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），通过桥接细胞固有与细胞外在 通过共同的机制，铁代谢的肿瘤性程序。