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

基本信息

批准号：
10666459
负责人：
Jerry Edward Chipuk
金额：
$ 48.26万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
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/10666459
关键词：
Address Antibodies Biological Assay Biology Cancer Biology Cancer Prognosis Cell Death Cell Death Induction Cell Line Cell Survival Cells Chronic Clinical Clustered Regularly Interspaced Short Palindromic Repeats Complex 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 Phenotype Process Prognosis Proliferating Publishing RNA Interference Regulation Resources Risk Signal Transduction Therapeutic Work 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 pharmacologic prevent prognostic prognostic assays prognostic value small molecule success targeted treatment tool tumor metabolism tumorigenesis tumorigenic

项目摘要

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事实上，线粒体畸变在细胞代谢、增殖、转移和细胞死亡中很常见。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细胞内的化疗成功产生负面影响。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。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，并且癌症表型在该 R01 中很少见。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。皮肤病学方面的专业知识和资源，我们将重点关注黑色素瘤的存在和 mtDNA 突变。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为了解决这一知识差距，我们最近进行了研究。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。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，经过多年的努力，该项目出现了，并提供了强大的预后价值和治疗潜力。确定慢性线粒体分裂如何影响癌症机制、预后和治疗。