Mitochondrial transfer from astrocytes to glioblastoma cells drives tumor growth

线粒体从星形胶质细胞转移到胶质母细胞瘤细胞驱动肿瘤生长

基本信息

批准号：
10579532
负责人：
Dionysios C Watson
金额：
$ 15.96万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-03 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10579532
关键词：
ATAC-seq Acetylation Address Affect Astrocytes Automobile Driving Biological Assay Biology Bone Marrow Brain Brain Neoplasms Cell Cycle Cell Lineage Cell Proliferation Cell model Cells Chemotherapy and/or radiation Chromatin Coculture Techniques Complex Cytoskeleton Data Development Disease Endogenous Retroviruses Endothelial Cells Endothelium Enzymes Epigenetic Process Fellowship Frequencies Future Gap Junctions Gene Expression Gene Expression Profile Genus Hippocampus Glioblastoma Glioma Goals Heterogeneity Histone Acetylation Human Hypoxia Immune Immunodeficient Mouse Immunotherapy In Vitro Knowledge Leukocytes Link Macrophage Malignant Neoplasms Malignant neoplasm of brain Mediating Mediator Mentorship Metabolic Metabolism Microglia Mitochondria Mitochondrial DNA Mitochondrial Proton-Translocating ATPases Mitosis Modality Modeling Molecular Morphology Mus Neuroglia Neurons Non-Malignant Operative Surgical Procedures Organelles Pathway interactions Patients Phase Phenotype Physicians Primary Brain Neoplasms Process Proliferating Proteins Radiation therapy Recurrence Reporter Research Resistance Role Scientist Shapes Sorting Specimen Stress Supporting Cell Testing Therapeutic Training Transgenic Mice Tumorigenicity brain cell cancer cell career career development cdc Genes chemotherapy design fluorophore genetic manipulation in vivo inhibitor insight knock-down metabolomics molecular targeted therapies mouse model neoplastic cell neural overexpression patient derived xenograft model progenitor programs purine/pyrimidine metabolism receptor self-renewal single-cell RNA sequencing spatiotemporal standard care stem stem cells syncytin therapeutic development therapeutic target therapy resistant transcriptome sequencing tumor tumor growth tumor metabolism tumor microenvironment

项目摘要

PROJECT SUMMARY: Glioblastoma (GBM) is the most common primary brain tumor and is incurable, invariably recuring after standard therapy with surgery, chemotherapy and radiation. GBM cell heterogeneity allows it to thrive in varying adverse conditions in the tumor microenvironment (TME), including therapeutic insults, hypoxic stress, and immune attack. Interactions with cells in the TME—including neurons, glia, endothelium, and immune cells—support this heterogeneity and plasticity, contributing to the tumorigenicity, resistance, and recurrence of this deadly disease. Given the limited efficacy of standard treatment approaches in GBM, there is an urgent need to decipher and therapeutically target protumorigenic interactions in the TME. There is evidence that glioma cells form an interconnected network that facilitates the exchange of mitochondria, which are the main energy-producing organelle and regulate metabolism, proliferation, and epigenetics. There is also early evidence that mitochondria can be transferred from non-malignant cells to cancer cells. However, there is limited understanding of mitochondrial transfer dynamics from the TME to GBM; the mechanisms that govern this transfer; and the downstream effects of transfer on recipient GBM cells. Addressing this knowledge gap is vital for designing therapeutics that target this interaction. I hypothesize that mitochondria are transferred from neural cells in the TME to GBM by the action of fusogenic proteins, and that this transfer drives tumorigenicity by metabolic and epigenetic reprogramming. Specific Aim 1 will test the hypothesis that astrocytes are the predominant mitochondrial donors, and that transfer is mediated by fusogenic proteins termed syncytins. I will investigate mitochondrial donor identity using transgenic mice and cell models expressing lineage-specific mitochondrial fluorophores. I will test how knockdown and overexpression of syncytins affects rate and protumorigenic effects of transfer from astrocytes to GBM cells. Specific Aim 2 will test the hypothesis that mitochondrial transfer from astrocytes drives GBM proliferation and tumorigenicity by metabolic and epigenetic reprogramming. I will investigate how transfer of ATP-synthase with mitochondria drives tumorigenicity; how mitochondrial transfer results in plasticity of GBM heterogeneity by global metabolic reprogramming; and how mitochondrial transfer drives proliferation by epigenetic reprogramming and increased chromatin accessibility. Career development and long-term objectives: I will receive training in cancer metabolism and brain tumor research, and interact with a mentorship committee of experts from both fields. This training and the proposed studies are invaluable for my career goal of establishing an independent research program with the following long-term objectives: (a) elucidate molecular mechanisms of how mitochondrial transfer reprograms metabolism and epigenetics, (b) develop therapeutics targeting mitochondrial transfer and its downstream effects, (c) investigate how metabolic interactions in the TME impact other treatment modalities, including chemotherapy, radiotherapy, and immunotherapy in GBM and other cancers.

项目摘要：胶质母细胞瘤 (GBM) 是最常见的原发性脑肿瘤，并且无法治愈，在手术、化疗和放疗等标准治疗后，GBM 细胞异质性总是会复发。使其能够在肿瘤微环境 (TME) 的各种不利条件下茁壮成长，包括治疗损伤、缺氧应激和免疫攻击与 TME 中的细胞（包括神经元、神经胶质细胞）的相互作用。内皮细胞和免疫细胞——支持这种异质性和可塑性，有助于致瘤性，鉴于标准治疗方法的疗效有限，这种致命疾病的耐药性和复发。在 GBM 中，迫切需要破译 TME 中的促肿瘤相互作用并进行治疗。有证据表明神经胶质瘤细胞形成一个互连的网络，促进线粒体的交换，它们是主要产生能量的细胞器，调节新陈代谢、增殖和表观遗传学。这也是线粒体可以从非恶性细胞转移到癌细胞的早期证据。对从 TME 到 GBM 的线粒体转移动力学的了解有限；控制这种转移的机制；以及转移对受体 GBM 细胞的下游影响。解决这一知识差距对于设计针对这种相互作用的疗法至关重要。线粒体通过融合蛋白的作用从 TME 中的神经细胞转移到 GBM，并且这种转移通过代谢和表观遗传重编程来驱动致瘤性，具体目标 1 将测试假设星形胶质细胞是主要的线粒体供体，并且转移是由融合介导的我将使用转基因小鼠和细胞模型研究线粒体供体身份。我将测试如何表达谱系特异性线粒体荧光团。合胞素会影响从星形胶质细胞转移到 GBM 细胞的速率和促肿瘤作用。具体目标 2 将。检验星形胶质细胞线粒体转移驱动 GBM 增殖和致瘤性的假设我将研究 ATP 合酶如何与线粒体转移。驱动致瘤性；线粒体转移如何通过整体代谢导致 GBM 异质性的可塑性重编程；以及线粒体转移如何通过表观遗传重编程驱动增殖并增加染色质可及性。职业发展和长期目标：我将接受癌症培训。新陈代谢和脑肿瘤研究，并与来自这两个领域的专家组成的指导委员会进行互动。培训和拟议的研究对于我建立独立研究的职业目标非常宝贵该计划具有以下长期目标：(a) 阐明线粒体如何转移重新编程代谢和表观遗传学，（b）开发针对线粒体转移的疗法和其下游影响，(c) 研究 TME 中的代谢相互作用如何影响其他治疗方式，包括 GBM 和其他癌症的化疗、放疗和免疫治疗。