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: 10154064
• 负责人: Connor Murphy
• 金额: $ 3.12万
• 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/10154064
• 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 多发性骨髓瘤（MM）的特征是恶性浆细胞主要在骨中扩增 5年生存率只有50%。肥胖增加MM发病率的风险， 对治疗的反应较差。事实上，肥胖是许多癌症的主要危险因素， 肥胖支持癌症发展和进展的一系列机制。一种机制可以 通过增加游离脂肪酸的可用性，其在肥胖人群的血浆中升高。 脂肪酸可以通过一种称为脂肪酸氧化的过程用作细胞的燃料来源。因此，基于 脂肪酸氧化在其他癌症中的作用，以及MM中的肥胖风险因素，我们假设脂肪酸氧化在MM中的作用是 酸和脂肪酸氧化促进MM进展。骨髓瘤细胞由许多因素支持， 骨髓微环境中的细胞。有趣的是，高达70%的骨髓是由黄色组成的。 肥胖和衰老（MM的另一个主要风险因素）会增加骨髓（脂肪）。黄色 骨髓由骨髓脂肪细胞（脂肪细胞）组成，其通常与骨髓瘤细胞相邻。我们的实验室， 和其他研究表明骨髓脂肪细胞驱动骨髓瘤对化疗药物的耐药性， 细胞因此，我们将检验脂肪酸氧化有助于骨髓瘤细胞存活和药物治疗的假设。 耐药性，骨髓脂肪细胞通过增加其 脂肪酸氧化，有以下两个目的。目的1）我们将检验脂肪酸氧化 通过抑制脂肪酸氧化的限速酶肉毒碱来支持骨髓瘤细胞， 棕榈酰转移酶1（CPT 1），通过遗传学或药理学方法，并测量骨髓瘤细胞 增殖/死亡、呼吸、代谢物和对地塞米松的反应。专门测试 某些脂质在脂肪酸氧化，我们将研究骨髓瘤细胞存活和药物治疗的变化。 对人血清和骨髓脂肪细胞中高度富集的脂质产生抗性。 目的2）我们将检验骨髓脂肪细胞增强骨髓瘤细胞脂肪酸氧化的假设， 通过共培养缺乏上述功能性CPT 1的骨髓瘤细胞或对照， 骨髓脂肪细胞和确定骨髓瘤细胞如何响应和代谢骨髓脂肪细胞- 衍生脂肪酸。综合起来，这些实验将阐明骨髓 脂肪细胞和脂肪酸氧化影响骨髓瘤细胞存活和药物抗性。