Chronic Mitochondrial Division and Melanoma: Mechanism, Prognosis, and Therapy

项目摘要 线粒体生物学对人类癌症的影响是广泛的，因为这些细胞器是关键的调节器 代谢、增殖、转移和细胞死亡。事实上，线粒体畸变在 多种癌症类型-线粒体功能障碍不仅与疾病发病机制相关， 线粒体也对化疗成功产生负面影响。在细胞内，线粒体的稳态 是由一个称为“线粒体动力学”的过程维持的，这是有效ATP所必需的。 生成、线粒体代谢物/底物分布和线粒体DNA（mtDNA）完整性。 稳态线粒体动力学是由线粒体的互补循环的累积性质引起的。 分裂与融合本实验室的工作表明：（1）线粒体分裂机制是必不可少的 对于细胞转化，（2）在RAS转化的鼠细胞中，线粒体分裂被长期激活 和在MAPK途径内携带致癌突变的人癌细胞系，（3）慢性线粒体 分裂足以引发线粒体功能障碍和癌细胞代谢，以及（4）FDA批准的 抑制致癌MAPK信号传导的靶向治疗关闭线粒体分裂机制。而 上述研究将慢性线粒体分裂与癌症生物学联系起来， 线粒体分裂促进细胞器功能障碍，并且癌症表型很少。在此R 01 应用程序，我们的目标是（1）提供关键的机械细节的过程和贡献， 致癌转化过程中线粒体功能障碍，以及（2）开发新的翻译工具，重点是 检测和抑制慢性线粒体分裂以增强癌症预后和治疗。作为我们 专家和资源都在皮肤科，我们将专注于黑色素瘤。线粒体DNA突变的存在， 癌症中的线粒体畸变已经描述了几十年，但是驱动这些的分子事件 变化及其对癌症生物学的影响仍然是推测性的。为了解决这一知识差距，我们最近 完成了一项使用正常黑色素细胞和黑色素瘤细胞系的无偏筛选，以了解慢性黑色素瘤 线粒体分裂对线粒体功能的影响，并确定功能丧失的mtDNA突变 是癌细胞代谢、增殖和肿瘤发生所必需的。我们假设癌基因- 诱导的慢性线粒体分裂促进mtDNA突变和细胞器异质性， 转型根据我们的数据，慢性线粒体分裂是黑色素瘤发生的早期事件， 并且提供了强的预后价值和治疗潜力。这个项目是经过多年的努力才出现的， 确定慢性线粒体分裂如何影响癌症机制，预后和治疗。

PROJECT SUMMARY The impact of mitochondrial biology on human cancers is broad because these organelles are critical regulators of metabolism, proliferation, metastasis, and cell death. Indeed, mitochondrial aberrations are common in multiple cancer types – not only do mitochondrial dysfunctions correlate with disease pathogenesis, but aberrant mitochondria also negatively impact upon chemotherapeutic success. Within a cell, mitochondrial homeostasis is maintained by a process referred to as “mitochondrial dynamics”, which is essential for efficient ATP generation, mitochondrial metabolites/substrates distribution, and mitochondrial DNA (mtDNA) integrity. Homeostatic mitochondrial dynamics result from the cumulative nature of complementary cycles of mitochondrial division and fusion. Work from my laboratory demonstrates: (1) the mitochondrial division machinery is essential for cellular transformation, (2) mitochondrial division is chronically activated in RAS-transformed murine cells and human cancer lines harboring oncogenic mutations within the MAPK pathway, (3) chronic mitochondrial division is sufficient to initiate mitochondrial dysfunction and cancer cell metabolism, and (4) FDA-approved targeted therapies that inhibit oncogenic MAPK signaling turn off the mitochondrial division machinery. While the above studies link chronic mitochondrial division to cancer biology, mechanistic explanations for how chronic mitochondrial division promotes organelle dysfunction and cancer phenotypes are scarce. In this R01 application, our goals are to (1) provide key mechanistic details into the process and contributions of mitochondrial dysfunction during oncogenic transformation, and (2) develop novel translational tools focused on the detection and inhibition of chronic mitochondrial division to enhance cancer prognosis and treatment. As our expertise and resources are in dermatology, we will focus on melanoma. The presence of mtDNA mutations and mitochondrial aberrations in cancer have been described for decades, but the molecular events that drive these changes and their impact on cancer biology remain speculative. To address this knowledge gap, we recently completed an unbiased screen using normal melanocytes and melanoma cell lines to understand how chronic mitochondrial division impacts on mitochondrial function, and identified that loss-of-function mtDNA mutations are essential for cancer cell metabolism, proliferation, and tumorigenesis. We hypothesize that oncogene- induced chronic mitochondrial division promotes mtDNA mutations and organelle heterogeneity to instigate transformation. Based on our data, chronic mitochondrial division is an early event during melanomagenesis, and provides strong prognostic value and therapeutic potential. This project emerged following years of effort to identify how chronic mitochondrial division impacts cancer mechanisms, prognosis, and treatment.