Determining the role of lipid droplets in glioblastoma and their therapeutic potential

确定脂滴在胶质母细胞瘤中的作用及其治疗潜力

• 批准号: 10433900
• 负责人: Deliang Guo
• 金额: $ 40.86万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-15 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10433900
• 关键词: Acetates; Address; Adult; Apoptosis; Autophagocytosis; Biology; Brain Neoplasms; Cell Death; Cell Survival; Cells; Cholesterol; Cholesterol Esters; Clinic; Combined Modality Therapy; DNA Repair; Data; Endoplasmic Reticulum; Energy-Generating Resources; Enzyme Inhibition; Enzymes; Esterification; Excision; Fatty Acids; Genetic; Glioblastoma; Glucose; Glutamine; Goals; Homeostasis; Hydrolysis; Impairment; Knowledge; Lead; Lipids; Lysosomes; Maintenance; Malignant Neoplasms; Malignant neoplasm of pancreas; Malignant neoplasm of prostate; Mediating; Membrane; Metabolism; Mitochondria; Molecular; Nonesterified Fatty Acids; Nutrient; Outcome; Patients; Pharmacology; Play; Prevention; Primary Brain Neoplasms; Production; Radiation; Regulation; Renal Cell Carcinoma; Reporting; Resistance; Resistance development; Role; Sampling; Starvation; Sterol O-Acyltransferase; Structure; Testing; Therapeutic; Toxic effect; Translating; Triglycerides; Tumor Tissue; base; brain cell; brain tissue; cancer cell; cancer therapy; diacylglycerol O-acyltransferase; endoplasmic reticulum stress; improved; inhibitor; insight; lipid metabolism; lipidomics; mouse model; neoplastic cell; novel; novel strategies; nutrient deprivation; oxidation; phase II trial; phase III trial; prevent; temozolomide; therapy resistant; treatment effect; tumor; tumor growth; tumor metabolism; uptake

ABSTRACT Glioblastoma (GBM) is the most aggressive brain tumor, and has a median survival of only 12-15 months despite intensive therapies, indicating the urgent need to identify effective approaches to treat GBM and circumvent resistance to therapies in order to significantly improve patient survival. Our recent studies demonstrated that lipid synthesis and uptake are greatly enhanced in GBM and promote tumor growth. It is known that increased free fatty acids (FFA) and cholesterol can cause endoplasmic reticulum (ER) stress and lipotoxicity that lead to cell death, which raises the intriguing question of how GBM cells can prevent the toxicity potentially induced by increased lipid metabolism. We recently found that tumor tissues from GBM patients contain large amount of lipid droplets (LDs), triglycerides (TG) and cholesteryl esters (CE), suggesting that GBM cells may store excess FFA and cholesterol into LDs to avoid toxicity and maintain tumor growth. Further analysis showed that GBM patients whose tumor tissues contained higher levels of LDs and of DGAT1 (diglyceride acyltransferase) or SOAT1 (sterol O-acyltransferase), two ER membrane-bound enzymes that catalyze the conversion of excess FFA and cholesterol into TG and CE to form LDs, had the worse survival, suggesting that LDs may have a protumoral function. Consistent with our findings, several groups have recently reported that inhibiting cholesterol esterification or suppressing LD formation in prostate, pancreatic or renal cancer cells significantly enhanced ER stress. Nevertheless, many important LD functions in cancer cells remain unexplored, such as their energetic role and potential for supporting tumor resistance. Our preliminary data suggest that LDs may provide a critical energy source for GBM survival under nutrient reduction or radiation/temozolomide (TMZ) treatment, the standard therapy for GBM. Based on current understanding of LDs in cancer cells and our novel preliminary data, we hypothesize that LD formation in GBM prevents ER stress and lipotoxicity, and also serves as energy reservoir to support tumor survival upon energy challenges. We further hypothesize that inhibiting LD formation will cause ER stress, lipotoxicity and energy shortage, which may strongly synergize with radiation/TMZ treatment to induce GBM cell death. In this study, we will: (1) delineate the underlying protective role of LD formation in GBM cells; (2) determine whether LDs play an important energetic role in GBM cells; (3) examine whether genetically or pharmacologically inhibiting LD formation effectively suppresses tumor growth and sensitizes GBM to radiation/TMZ treatment in GBM orthotopic mouse models. This study will reveal the previously uncharacterized role and molecular regulation of LDs in GBM. Importantly, it will also demonstrate that inhibiting LD formation may be a very effective approach to specifically target GBM with little toxicity on normal brain tissues where no LDs could be detected. Completion of this study will significantly advance our understanding of lipid metabolism reprogramming and may bring about new approaches to antagonize GBM.

抽象的 胶质母细胞瘤（GBM）是最具侵略性的脑肿瘤，尽管 强化疗法，表明迫切需要确定有效的方法来治疗GBM和绕过 对疗法的耐药性，以显着提高患者的生存率。我们最近的研究表明 脂质合成和摄取在GBM中大大增强并促进肿瘤生长。众所周知 游离脂肪酸（FFA）和胆固醇会引起内质网（ER）胁迫和脂肪毒性，导致导致 细胞死亡提出了一个有趣的问题，即GBM细胞如何防止可能引起的毒性 脂质代谢增加。我们最近发现，来自GBM患者的肿瘤组织包含大量 脂质液滴（LDS），甘油三酸酯（TG）和胆固醇酯（CE），表明GBM细胞可能存储过多 FFA和胆固醇成LDS，以避免毒性并维持肿瘤的生长。进一步分析表明GBM 肿瘤组织含有较高水平的LDS和DGAT1（二甘油类酰基转移酶）或 SOAT1（固醇O-酰基转移酶），两个ER膜结合的酶，可催化过量的转化 FFA和胆固醇成TG和CE形成LDS，生存较差，表明LDS可能具有 原始功能。与我们的发现一致，几个小组最近报告说抑制胆固醇 酯化或抑制前列腺，胰腺或肾癌细胞中的LD形成显着增强了ER 压力。然而，癌细胞中许多重要的LD功能仍未探索，例如 能量和支持肿瘤耐药性的潜力。我们的初步数据表明LDS可能 在营养减少或辐射/替莫唑胺（TMZ）下，提供了GBM生存的关键能源 治疗，GBM的标准疗法。基于当前对癌细胞中LDS的理解和我们的新颖 初步数据，我们假设GBM中的LD形成可防止ER应力和脂肪毒性，并且也有效 作为支持肿瘤生存在能量挑战方面的能量储层。我们进一步假设抑制 LD形成会导致ER应力，脂肪毒性和能量短缺，这可能会与 辐射/TMZ处理可诱导GBM细胞死亡。在这项研究中，我们将：（1）描绘基础保护性 LD形成在GBM细胞中的作用； （2）确定LD在GBM细胞中是否起重要的能量作用； （3） 检查遗传或药理抑制LD形成是否有效抑制肿瘤生长 并将GBM敏感到GBM原位小鼠模型中的辐射/TMZ处理。这项研究将揭示 LDS在GBM中的先前未表征和分子调节。重要的是，它也将证明 抑制LD形成可能是一种非常有效的方法，可以专门针对GBM，而毒性很少 正常的脑组织无法检测到LDS。这项研究的完成将大大推动我们的 了解脂质代谢重编程，并可能带来与GBM拮抗的新方法。