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.

项目摘要线粒体生物学对人类癌症的影响很广，因为这些细胞器是关键的调节剂代谢，增殖，转移和细胞死亡。确实，线粒体畸变在多种癌症类型 - 不仅线粒体功能障碍与疾病发病机理相关，而且异常线粒体也对化学治疗成功产生负面影响。在细胞内，线粒体稳态由称为“线粒体动力学”的过程维护，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。稳态线粒体动力学是由于线粒体完整周期的累积性质而产生的分区和融合。我的实验室的工作证明：（1）线粒体划分机械是必不可少的对于细胞转化，（2）线粒体分裂在RAS转换的鼠细胞中长期激活和在MAPK途径内具有致癌突变的人类癌细胞系，（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，并且（4）FDA批准抑制致癌MAPK信号传导的靶向疗法关闭线粒体分裂机械。而以上研究将慢性线粒体分裂与癌症生物学联系起来，对慢性的机理解释线粒体分裂可促进细胞器功能障碍，癌症表型稀缺。在此R01中应用，我们的目标是（1）为过程和贡献提供关键的机械细节线粒体功能障碍在致癌过程中，以及（2）开发针对的新型翻译工具慢性线粒体分裂的检测和抑制以增强癌症的预后和治疗。作为我们的专业知识和资源是皮肤病学的，我们将专注于黑色素瘤。 MtDNA突变的存在和数十年来已经描述了癌症的线粒体畸变，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投机性的。为了解决这个知识差距，我们最近使用正常黑色素细胞和黑色素瘤细胞系完成了公正的屏幕，以了解慢性线粒体分裂对线粒体功能的影响，并确定功能丧失mtDNA突变我们假设癌基因 - 诱导的慢性线粒体分裂促进mtDNA突变和细胞器异质性，以激发转型。基于我们的数据，慢性线粒体分裂是梅洛米发生的早期事件，并提供强大的预后价值和治疗潜力。该项目经过多年的努力而出现确定慢性线粒体分裂如何影响癌症机制，预后和治疗。