Lipid Metabolism-driven Drug Resistance in Multiple Myeloma

脂质代谢驱动的多发性骨髓瘤耐药性

基本信息

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
项目类别：
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

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

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项目摘要

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）的特征是恶性血浆细胞的扩张主要在骨骼中骨髓，5年生存率仅为50％。肥胖增加了MM发病率的风险，并预测对治疗的反应较差。实际上，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展和进展的各种机制。一种机制可以通过增加的游离脂肪酸的可用性，肥胖者的血浆中升高。通过称为脂肪酸氧化的过程，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肥胖风险因素在MM中的作用，我们假设脂肪酸和脂肪酸氧化有助于MM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，多达70％的骨髓由黄色组成（脂肪）骨髓，肥胖和衰老（MM的另一个主要危险因素）。黄色的骨髓由通常与骨髓瘤细胞相邻的骨髓脂肪细胞（脂肪细胞）组成。我们的实验室还有其他，已经表明骨髓脂肪细胞驱动对骨髓瘤化学治疗剂的抗性细胞。因此，我们将测试脂肪酸氧化有助于骨髓瘤细胞存活和药物的假设抗性，骨髓脂肪细胞通过增加其骨髓瘤细胞耐药性在以下两个目标中，脂肪酸氧化。目的1）我们将检验脂肪酸氧化的假设通过抑制用于脂肪酸氧化的限制酶来支持骨髓瘤细胞。通过遗传或药理方法和测量骨髓瘤细胞，棕榈酰转移酶1（CPT1）增殖/死亡，呼吸，代谢产物以及对地塞米松的反应。专门测试脂肪酸氧化中的某些脂质，我们将研究骨髓瘤细胞存活和药物的变化响应于高度富含人血清和骨髓脂肪细胞的脂质的抗性。目标2）我们将检验以下假设：骨髓脂肪细胞增强骨髓瘤细胞脂肪酸氧化，生存和耐药性通过共同培养的骨髓瘤细胞缺乏上述功能性CPT1，或与对照骨髓脂肪细胞并确定骨髓瘤细胞如何反应并代谢骨髓脂肪细胞 - 衍生的脂肪酸。综上所述，这些实验将阐明骨髓的机制脂肪细胞和脂肪酸氧化会影响骨髓瘤细胞的存活和耐药性。