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.

项目概要 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因子 代谢、增殖、转移和细胞死亡。事实上，线粒体畸变常见于 多种癌症类型——线粒体功能障碍不仅与疾病发病机制相关，而且与疾病发病机制相关 线粒体也会对化疗的成功产生负面影响。在细胞内，线粒体稳态 由称为“线粒体动力学”的过程维持，这对于有效的 ATP 至关重要 生成、线粒体代谢物/底物分布和线粒体 DNA (mtDNA) 完整性。 线粒体稳态动力学是由线粒体互补循环的累积性质引起的 分裂与融合。我实验室的工作表明：（1）线粒体分裂机制至关重要 对于细胞转化，(2) RAS 转化的小鼠细胞中线粒体分裂长期被激活 和 MAPK 途径中含有致癌突变的人类癌症系，(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，并且 (4) FDA 批准 抑制致癌 MAPK 信号传导的靶向疗法会关闭线粒体分裂机制。虽然 上述研究将慢性线粒体分裂与癌症生物学联系起来，解释了慢性线粒体分裂是如何发生的。 线粒体分裂促进细胞器功能障碍，癌症表型很少。在这个R01 应用程序，我们的目标是（1）提供关键的机制细节到过程和贡献 致癌转化过程中线粒体功能障碍，以及（2）开发新的转化工具，重点关注 检测和抑制慢性线粒体分裂，以增强癌症预后和治疗。作为我们的 专业知识和资源都在皮肤科，我们将重点关注黑色素瘤。线粒体DNA突变的存在和 癌症中的线粒体畸变已经被描述了数十年，但驱动这些畸变的分子事件 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 使用正常黑色素细胞和黑色素瘤细胞系完成了无偏见的筛选，以了解慢性 线粒体分裂影响线粒体功能，并发现功能丧失的 mtDNA 突变 对于癌细胞代谢、增殖和肿瘤发生至关重要。我们假设癌基因- 诱导的慢性线粒体分裂促进线粒体DNA突变和细胞器异质性 转变。根据我们的数据，慢性线粒体分裂是黑色素瘤发生过程中的早期事件， 并提供强大的预后价值和治疗潜力。经过多年的努力，这个项目应运而生 确定慢性线粒体分裂如何影响癌症机制、预后和治疗。