Mitochondrial Dynamics in Brain TumorInitiating Cells

摘要 胶质母细胞瘤是最致命的癌症之一，几十年的研究只增加了几个月 与这些肿瘤患者的中位生存期之间的关系。目前治疗的局限性有许多 原因，但一个促成因素是复杂的细胞异质性的存在， 正常的大脑层次结构在这个层次中的正常组织特异性干细胞由于它们的 持续增殖的能力。在健康组织中，干细胞存在于特定的小生境中， 维持信号，限制增殖，这些相同的细胞分化后退出龛。的 干细胞微环境与氧气、pH和营养物质可用性的区域变化有关。 因此，几乎可以肯定，在肿瘤发生的背景下发生的代谢重编程 代表了癌症干细胞生态位的一个元素。由于线粒体形态与代谢有关， 容量和谱系规范，我们正在研究线粒体动力学在驱动中的作用 生物能量变化促进癌症干细胞生长和增殖。在初步研究中，神经胶质瘤 发现干细胞表现出线粒体分裂的分子调节，这与非干细胞不同。 干肿瘤细胞和神经祖细胞。由于靶向线粒体动力学与神经元 我们提出，针对线粒体动力学的这种异质性， 可能代表了神经胶质瘤干细胞的选择性脆弱点。在建议的研究中，我们会 研究线粒体分裂在维持癌症干细胞健康中的作用， 模态总的来说，成功完成拟议的实验将提供一个增强的模型， 神经胶质瘤的分级和驱动新的临床治疗的发展。

ABSTRACT Glioblastomas rank among the most lethal of cancers with decades of research adding only a few months to the median survival of patients afflicted with these tumors. The limitations in current therapy have many causes, but one contributing force is the presence of complex cellular heterogeneity that phenocopies the normal brain hierarchy. Normal tissue specific stem cells within this hierarchy pose a danger due to their ability to undergo sustained proliferation. In healthy tissues, stem cells reside in specific niches that provide maintenance cues that constrain proliferation, and these same cells differentiate upon exiting the niche. The stem cell microenvironment is associated with regional variation in oxygen, pH, and nutrient availability. Thus, it is almost certain that the metabolic reprogramming that occurs within the context of oncogenesis represents an element of the cancer stem cell niche. As mitochondrial morphology is linked to metabolic capacity and lineage specification, we are investigating the role of mitochondrial dynamics in driving bioenergetic changes that promote cancer stem cell growth and proliferation. In preliminary studies, glioma stem cells were found to exhibit molecular regulation of mitochondrial fission that was distinct from non- stem tumor cells and neuroprogenitors. As targeting mitochondrial dynamics has been linked to neural protection in degenerative disease, we propose that targeting this heterogeneity in mitochondrial dynamics may represent a selective point of vulnerability for glioma stem cells. In the proposed studies, we will investigate the role of mitochondrial fission in sustaining cancer stem cell health and as a therapeutic modality. Collectively, successful completion of the proposed experiments will provide an enhanced model of glioma hierarchy and drive the development of novel clinical therapies.