Mitochondrial transfer from astrocytes to glioblastoma cells drives tumor growth

项目简介：胶质母细胞瘤(GBM)是最常见的原发脑肿瘤，不治之症。 在手术、化疗和放疗的标准治疗后，总是会复发。GBM细胞异质性 使其在肿瘤微环境(TME)中的各种不利条件下茁壮成长，包括治疗 侮辱、低氧压力和免疫攻击。与TME内细胞的相互作用--包括神经元、神经胶质细胞、 内皮和免疫细胞--支持这种异质性和可塑性，有助于肿瘤的发生， 这种致命疾病的抗药性和复发。鉴于标准治疗方法的疗效有限 在GBM中，迫切需要破译和治疗TME中的促肿瘤相互作用。 有证据表明，胶质瘤细胞形成了一个相互连接的网络，促进了线粒体的交换， 它们是产生能量的主要细胞器，调节新陈代谢、增殖和表观遗传学。那里 也是线粒体可以从非恶性细胞转移到癌细胞的早期证据。然而， 对线粒体从TME到GBM的转移动力学的了解有限； 管理这种转移的机制；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。我假设 在融合蛋白的作用下，线粒体从TME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新编程来驱动肿瘤的发生。《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，并且转移是由融合基因介导的 被称为合胞素的蛋白质。我将使用转基因小鼠和细胞模型来研究线粒体供体的身份 表达谱系特异的线粒体荧光团。我将测试击倒和过度表达 合胞素影响星形胶质细胞向GBM细胞转移的速率和促肿瘤效应。特定目标2将 验证星形胶质细胞线粒体转移通过以下途径驱动GBM增殖和致瘤性的假说 代谢和表观遗传重新编程。我将研究ATP合酶如何与线粒体转移 推动肿瘤发生；线粒体转移如何通过全球代谢导致GBM异质性的可塑性 重新编程；以及线粒体转移如何通过表观遗传重新编程和增加 染色质可及性。职业发展和长期目标：我将接受癌症方面的培训 新陈代谢和脑瘤研究，并与来自这两个领域的专家指导委员会互动。这 培训和拟议的研究对于我建立独立研究的职业目标来说是非常宝贵的 有以下长期目标的计划：(A)阐明线粒体如何 转移重新编程新陈代谢和表观遗传学，(B)开发针对线粒体转移和 其下游影响，(C)调查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、放射治疗和免疫治疗。

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.