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

慢性线粒体分裂和黑色素瘤：机制、预后和治疗

• 批准号: 10464554
• 负责人: Jerry Edward Chipuk
• 金额: $ 49.24万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-15 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10464554
• 关键词: Address; Antibodies; Biological Assay; Biology; Cancer Biology; Cancer Prognosis; Cell Death; Cell Line; Cell Survival; Cells; Chronic; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Complex; DNA sequencing; Data; Dermatology; Detection; Development; Disease; Event; FDA approved; Functional disorder; Generations; Genes; Genomics; Goals; Heterogeneity; Homeostasis; Human; Knowledge; Laboratories; Link; MAP Kinase Gene; Malignant - descriptor; Malignant Neoplasms; Melanoma Cell; Metabolic; Metabolism; Mitochondria; Mitochondrial DNA; Modeling; Molecular; Monoclonal Antibodies; Mus; Mutation; Nature; Neoplasm Metastasis; Oncogenes; Oncogenic; Organelles; Pathogenesis; Pathway interactions; Pharmacology; Phenotype; Process; Prognosis; Publishing; RNA Interference; Regulation; Resources; Risk; Signal Transduction; Therapeutic; Work; base; cancer cell; cancer therapy; cancer type; improved; insight; loss of function; melanocyte; melanoma; melanomagenesis; metabolomics; metaplastic cell transformation; mitochondrial DNA mutation; mitochondrial dysfunction; next generation; novel; prevent; prognostic; prognostic assays; prognostic value; small molecule; success; targeted treatment; tool; tumor metabolism; tumorigenesis; tumorigenic

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.

项目总结 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。 新陈代谢、增殖、转移和细胞死亡。事实上，线粒体异常在 多种癌症类型-线粒体功能障碍不仅与疾病的发病机制相关，而且还与异常相关 线粒体对化疗的成功也有负面影响。在细胞内，线粒体动态平衡 由一种被称为“线粒体动力学”的过程维持，这对有效的三磷酸腺苷是必不可少的。 线粒体代谢物/底物分布，以及线粒体DNA(MtDNA)的完整性。 线粒体动态平衡源于线粒体互补循环的累积性 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转化的小鼠细胞中线粒体分裂被慢性激活 和在MAPK通路中存在致癌突变的人类癌细胞系，(3)慢性线粒体 分裂足以启动线粒体功能障碍和癌细胞代谢，以及(4)FDA批准 抑制致癌MAPK信号的靶向治疗关闭了线粒体分裂机制。而当 上述研究将慢性线粒体分裂与癌症生物学联系起来，这是对慢性程度的机械解释 线粒体分裂促进细胞器功能障碍，癌症表型很少见。在本R01中 应用程序，我们的目标是(1)提供有关过程和贡献的关键机制细节 致癌转化过程中的线粒体功能障碍，以及(2)开发专注于 检测和抑制慢性线粒体分裂以提高癌症预后和治疗。作为我们的 专业知识和资源在皮肤科，我们将专注于黑色素瘤。线粒体DNA突变的存在和 几十年来，人们一直在描述癌症中的线粒体异常，但驱动这些异常的分子事件 这些变化及其对癌症生物学的影响仍然是推测的。为了解决这一知识差距，我们最近 使用正常黑素细胞和黑色素瘤细胞系完成无偏倚筛查，以了解慢性 线粒体分裂对线粒体功能的影响，并发现功能丧失的mtDNA突变 对于癌细胞的新陈代谢、增殖和肿瘤的形成是必不可少的。我们假设致癌基因- 诱导线粒体慢性分裂促进线粒体DNA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， 具有很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。