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 这些肿瘤患者的中位存活率。目前的治疗方法有很多局限性。 原因，但一个促成因素是复杂的细胞异质性的存在，这种现象复制 正常的大脑层次结构。这种层次结构中的正常组织特异性干细胞构成了危险，因为它们的 能够经历持续的扩散。在健康组织中，干细胞驻留在特定的利基环境中，为 抑制增殖的维持信号，这些相同的细胞在离开利基时分化。这个 干细胞微环境与氧、pH和营养可利用性的区域差异有关。 因此，几乎可以肯定的是，在肿瘤发生的背景下发生的代谢重新编程 代表了癌症干细胞利基的一种成分。因为线粒体形态与代谢有关 能力和谱系特征，我们正在研究线粒体动力学在驱动 促进癌症干细胞生长和增殖的生物能量变化。在初步研究中，胶质瘤 干细胞表现出与非干细胞不同的线粒体分裂的分子调控。 干细胞、肿瘤细胞和神经前体细胞。作为靶点，线粒体动力学已经与神经联系在一起 对于退行性疾病的保护，我们建议针对线粒体动力学中的这种异质性 可能代表了胶质瘤干细胞的一个选择性易损点。在建议的研究中，我们会 研究线粒体分裂在维持肿瘤干细胞健康和作为一种治疗手段中的作用 情态。总的来说，拟议实验的成功完成将提供一个增强的模型 并推动新的临床治疗方法的发展。

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.