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Differential role of different NAD+ kinase Isoforms in melanoma metastasis

不同 NAD 激酶亚型在黑色素瘤转移中的不同作用

基本信息

批准号：
10436014
负责人：
Elena Piskounova
金额：
$ 38.77万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
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：
2022-05-01 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10436014
关键词：
Adopted Affinity Chromatography Anoikis Antioxidants Automobile Driving Binding Blood Circulation Cancer Etiology Cancer Patient Cancer cell line Carbon Cell Line Cells Cessation of life ChIP-seq Clustered Regularly Interspaced Short Palindromic Repeats Cytoplasm Data Dependence Disease Disease Outcome Environment Enzymes Event Genetic Homeostasis Human Immunocompromised Host In Situ Malignant Neoplasms Malignant neoplasm of pancreas Melanoma Cell Metabolic Metabolic Pathway Metastatic to Mitochondria Modeling Molecular Mus Mutation NAD+ kinase NADP Nature Neoplasm Circulating Cells Neoplasm Metastasis Nodule Normal Cell Normal tissue morphology Organ Organelles Oxidation-Reduction Oxidative Stress Pathway interactions Patient-Focused Outcomes Patients Physiological Primary Neoplasm Production Protein Isoforms Protein Sequence Analysis Reactive Oxygen Species Reduced Glutathione Regulation Regulatory Element Reporter Resistance Role Signal Transduction Stress Testing Therapeutic Intervention Transcription Initiation Site Transcriptional Regulation Up-Regulation Visceral Work cancer cell cancer survival cell regeneration cell type clinical predictors clinically relevant effective therapy experience in vitro Model in vivo melanoma metabolic profile migration mortality mouse model neoplastic cell new therapeutic target novel overexpression patient derived xenograft model promoter response sensor subcutaneous targeted treatment transcription factor tumor

项目摘要

PROJECT SUMMARY Metastasis is responsible for more than 90% of cancer patient mortality yet there are no therapies that specifically target metastatic disease. Many of the current in vitro models of metastasis focus on the molecular mechanisms of migration, invasion and/or surviving anoikis, but cannot recapitulate the complexity of the environment in which metastasis occurs in vivo. Conversely, in mouse models of metastasis, it has been difficult to examine the molecular mechanisms that enable cells to proceed through each distinct step of metastasis due to limited material that can be isolated and infrequency of metastatic events in these models. For these reasons little is known about the challenges facing metastasizing cells in vivo, and how they are overcome. We have previously established a clinically relevant model of melanoma metastasis, using patient-derived xenografts (PDX) in immunocompromised mice, that recapitulates the outcome of the disease of the patient in mice, to dissect the metastatic cascade into distinct steps. Using this model, we have shown that metastasizing melanoma cells undergo reversible metabolic adaptations to withstand oxidative stress in part through an increased dependence on NADPH-generating enzymes in the one-carbon pathway. Our preliminary data also show an increase in NADP+ levels in metastatic nodules compared to subcutaneous tumors, suggesting an increase in de novo NADP+ synthesis. NADP+ is generated from NAD+ by NAD+ kinase (NADK). We observe higher levels of NADK in metastatic nodules compared to subcutaneous tumors, where metastatic nodules express the isoform of NADK with the highest activity, while subcutaneous tumors do not. We will test the hypothesis that metastasizing melanoma cells upregulate a specific isoform of NADK to increase NADP+ production, increase oxidative stress resistance and survival at different steps of the metastatic cascade. Using both melanoma cell lines and PDX tumor cells, Aim 1 will determine the role of different NADK isoforms in oxidative stress resistance, Aim 2 will define the mechanism of transcriptional regulation of NADK isoforms, and Aim 3 will establish the role of different NADK isoforms as metastatic drivers in vivo. In addition, Aim 3 will test how perturbation of oxidative stress in different organelles impacts metastasis. Together this work will significantly contribute to our understanding of a novel mechanism of metabolic plasticity through upregulation of a specific NADK isoform and identify organelle-specific metabolic pathways as novel therapeutically targetable vulnerabilities in melanoma metastasis.

项目总结