Lipid Metabolism-driven Drug Resistance in Multiple Myeloma

脂质代谢驱动的多发性骨髓瘤耐药性

• 批准号: 10334473
• 负责人: Connor Murphy
• 金额: $ 3.19万
• 依托单位: MAINEHEALTH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-18 至 2024-04-06
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10334473
• 关键词: Acids; Acyl Coenzyme A; Adipocytes; Adipose tissue; Adult; Affect; Age; Aging; Apoptosis; Biological Assay; Bone Marrow; Cancerous; Carbon Dioxide; Carnitine Palmitoyltransferase I; Cell Count; Cell Line; Cell Proliferation; Cell Survival; Cells; Cellular Assay; Cessation of life; Coculture Techniques; Coenzyme A Ligases; Data; Development; Dexamethasone; Drug resistance; Energy-Generating Resources; Enzymes; Epidemiology; Fatty Acids; Fatty acid glycerol esters; Gene Expression; Genetic; Glucocorticoids; Goals; Growth; Human; Hypertrophy; Hypoxia; In Vitro; Incidence; Incubated; Label; Link; Lipids; Malignant - descriptor; Malignant Neoplasms; Marrow; Mass Spectrum Analysis; Measures; Mesenchymal; Metabolic Pathway; Metabolism; Methods; Multiple Myeloma; Nonesterified Fatty Acids; Obesity; Oleates; Output; Oxidative Stress; Pharmacology; Phenotype; Plasma; Plasma Cells; Process; Production; Reactive Oxygen Species; Resistance; Respiration; Risk; Risk Factors; Role; Serum; Signal Transduction; Silk; Source; Supporting Cell; Survival Rate; Testing; Tissue Engineering; Visceral; Work; Yellow Marrow; adipocyte differentiation; adipokines; base; biological adaptation to stress; bone cell; cancer cell; chemotherapeutic agent; chemotherapy; cytokine; experimental study; fatty acid metabolism; fatty acid oxidation; high body mass index; innovation; insight; knock-down; lipid metabolism; migration; neoplastic cell; novel; obese person; obesity risk; progenitor; protein expression; response; small hairpin RNA; stem; subcutaneous; three dimensional cell culture; treatment response; triacsin C; tumor microenvironment; two-dimensional

Abstract Multiple myeloma (MM) is characterized by the expansion of malignant plasma cells primarily in the bone marrow and has a 5-year survival rate of only 50%. Obesity increases the risk of MM incidence and predicts a poorer response to treatment. In fact, obesity is a major risk factor for many cancers, and there are likely an array of mechanisms by which obesity supports cancer development and progression. One mechanism may be through the increased availability of free fatty acids, which are elevated in the plasma of obese people. Fatty acids can be used as a fuel source for cells through a process called fatty acid oxidation. Thus, based on the role of fatty acid oxidation in other cancers, and the obesity risk factor in MM, we hypothesize that fatty acids and fatty acid oxidation contribute to MM progression. Myeloma cells are supported by many factors and cells in the bone marrow microenvironment. Interestingly, up to 70% of the bone marrow is composed of yellow (fatty) marrow, which is increased in obesity, as well as aging (another major risk factor for MM). Yellow marrow is composed of bone marrow adipocytes (fat cells), which are often adjacent to myeloma cells. Our lab, and others, have shown that bone marrow adipocytes drive resistance to chemotherapeutic agents in myeloma cells. Thus, we will test the hypothesis that fatty acid oxidation contributes to myeloma cell survival and drug resistance, and that bone marrow adipocytes support myeloma cell drug resistance through increasing their fatty acid oxidation, in the following two Aims. Aim 1) We will test the hypothesis that fatty acid oxidation supports myeloma cells by inhibiting the rate-limiting enzyme for fatty acid oxidation, carnitine- palmitoyltransferase 1 (CPT1), through genetic or pharmacological methods, and measuring myeloma cell proliferation/death, respiration, metabolites, and responses to dexamethasone. To specifically test the roles of certain lipids in fatty acid oxidation, we will investigate the changes in myeloma cell survival and drug resistance in response to lipids that are highly enriched in human serum and from bone marrow adipocytes. Aim 2) We will test the hypothesis that bone marrow adipocytes enhance myeloma cell fatty acid oxidation, survival, and drug resistance by co-culturing myeloma cells lacking functional CPT1 as above, or controls, with bone marrow adipocytes and identifying how myeloma cells respond and metabolize bone marrow adipocyte- derived fatty acids. Taken together, these experiments will elucidate the mechanisms of how bone marrow adipocytes and fatty acid oxidation affect myeloma cell survival and drug resistance.

摘要