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，是无法治愈的，通过手术，化学疗法和放疗后标准治疗后，始终会重复出现。 GBM细胞异质性允许它在肿瘤微环境（TME）中在不同的不良条件下壮成长，包括治疗侮辱，低氧压力和免疫攻击。与TME中细胞的相互作用 - 包括神经元，神经胶质，内皮和免疫电池 - 支持这种异质性和可塑性，导致肿瘤性，这种致命疾病的抵抗和复发。鉴于标准治疗方法的效率有限在GBM中，迫切需要破译和治疗靶向TME中的杂种相互作用。有证据表明，神经胶质瘤细胞形成一个相互联系的网络，可促进线粒体的交换，这是产生能量的主要细胞器，并调节代谢，增殖和表观遗传学。那里也是早期证据表明线粒体可以从非恶性细胞转移到癌细胞。然而，从TME到GBM的线粒体转移动力学的理解有限。控制这种转移的机制；以及转移对受体GBM细胞的下游影响。解决此知识差距对于设计针对这种相互作用的治疗至关重要。我假设这一点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促进了肿瘤性。特定目标1将测试假设星形胶质细胞是主要的线粒体供体，并且该转移是由菌源介导的蛋白质称为Syncines。我将使用转基因小鼠和细胞模型研究线粒体供体的身份表达谱系特异性线粒体荧光团。我将测试如何敲低和过表达合成蛋白会影响从星形胶质细胞转移到GBM细胞的速率和原始作用。具体目标2将检验了从星形胶质细胞转移线粒体的假设代谢和表观遗传重编程。我将研究如何用线粒体转移ATP合成酶驱动肿瘤性；线粒体转移如何导致全球代谢的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和增加来驱动增殖染色质可及性。职业发展和长期目标：我将接受癌症的培训代谢和脑肿瘤研究，并与来自两个领域的专家的指导委员会互动。这培训和拟议的研究对于我的职业目标是建立独立研究的目标是无价的具有以下长期目标的程序：（a）阐明线粒体的分子机制转移重编程的代谢和表观遗传学，（b）开发针对线粒体转移的理论和它的下游效应，（c）研究TME中的代谢相互作用如何影响其他治疗方式，包括化学疗法，放疗和GBM和其他癌症的免疫疗法。