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.

抽象的 多发性骨髓瘤 (MM) 的特点是恶性浆细胞主要在骨中扩张 骨髓，5年生存率仅为50%。肥胖会增加 MM 发病的风险并预测 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，并且可能有 肥胖支持癌症发生和进展的一系列机制。一种机制可能 是通过增加游离脂肪酸的可用性来实现的，肥胖者血浆中的游离脂肪酸含量升高。 通过脂肪酸氧化过程，脂肪酸可以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 中的肥胖危险因素，我们假设脂肪 酸和脂肪酸氧化有助于 MM 的进展。骨髓瘤细胞受到许多因素的支持 骨髓微环境中的细胞。有趣的是，高达 70% 的骨髓由黄色组成 （脂肪）骨髓，在肥胖和衰老（多发性骨髓瘤的另一个主要危险因素）中会增加。黄色的 骨髓由骨髓脂肪细胞（脂肪细胞）组成，通常与骨髓瘤细胞相邻。我们的实验室， 等人表明，骨髓脂肪细胞会导致骨髓瘤对化疗药物产生耐药性 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的假设 耐药性，并且骨髓脂肪细胞通过增加其耐药性来支持骨髓瘤细胞耐药性 脂肪酸氧化，有以下两个目的。目标 1) 我们将检验脂肪酸氧化的假设 通过抑制脂肪酸氧化限速酶肉毒碱来支持骨髓瘤细胞 棕榈酰转移酶1（CPT1），通过遗传或药理学方法，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。专门测试角色 某些脂质在脂肪酸氧化中，我们将研究骨髓瘤细胞存活和药物的变化 对人类血清和骨髓脂肪细胞中高度富集的脂质做出反应的抵抗力。 目标 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， 通过与上述缺乏功能性 CPT1 的骨髓瘤细胞或对照细胞共培养来提高生存率和耐药性 骨髓脂肪细胞并确定骨髓瘤细胞如何反应和代谢骨髓脂肪细胞- 衍生脂肪酸。总而言之，这些实验将阐明骨髓如何 脂肪细胞和脂肪酸氧化影响骨髓瘤细胞的存活和耐药性。