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

基本信息

批准号：
10201766
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
项目类别：
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/10201766
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/antagonist 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

项目摘要

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) 是最具侵袭性的脑肿瘤，尽管其中位生存期仅为 12-15 个月，强化治疗，表明迫切需要找到治疗 GBM 和规避的有效方法从而显着提高患者的生存率。我们最近的研究表明 GBM 中的脂质合成和摄取大大增强，并促进肿瘤生长。据了解，增加了游离脂肪酸 (FFA) 和胆固醇可引起内质网 (ER) 应激和脂毒性，从而导致细胞死亡，这就提出了一个有趣的问题：GBM 细胞如何防止细胞死亡可能引起的毒性？脂质代谢增加。我们最近发现GBM患者的肿瘤组织中含有大量脂滴（LD）、甘油三酯（TG）和胆固醇酯（CE），表明GBM细胞可能储存过量 FFA 和胆固醇进入 LD 以避免毒性并维持肿瘤生长。进一步分析表明，GBM 肿瘤组织中 LD 和 DGAT1（甘油二酯酰基转移酶）水平较高的患者或 SOAT1（甾醇 O-酰基转移酶），两种 ER 膜结合酶，可催化过量的转化 FFA 和胆固醇转化为 TG 和 CE 形成 LD，其存活率较差，这表明 LD 可能具有促肿瘤功能。与我们的发现一致，几个小组最近报告说，抑制胆固醇前列腺、胰腺或肾癌细胞中的酯化或抑制 LD 形成可显着增强 ER 压力。然而，癌细胞中许多重要的 LD 功能仍未被探索，例如它们的支持肿瘤抵抗的积极作用和潜力。我们的初步数据表明 LD 可能在营养减少或辐射/替莫唑胺 (TMZ) 下为 GBM 生存提供关键能量来源治疗，GBM 的标准治疗。基于目前对癌细胞中 LD 的了解以及我们的新颖根据初步数据，我们假设 GBM 中 LD 的形成可以防止 ER 应激和脂毒性，并且还可以作为能量储存库，支持肿瘤在能量挑战下生存。我们进一步假设抑制 LD的形成会导致内质网应激、脂毒性和能量短缺，这可能与放射/TMZ 治疗诱导 GBM 细胞死亡。在本研究中，我们将：（1）描绘潜在的保护作用 GBM细胞中LD形成的作用； (2)确定LDs是否在GBM细胞中发挥重要的能量作用； (3) 检查基因或药理学抑制 LD 形成是否能有效抑制肿瘤生长并使 GBM 原位小鼠模型中的 GBM 对放射/TMZ 治疗敏感。这项研究将揭示 LDs 在 GBM 中的先前未表征的作用和分子调控。重要的是，它还将展示抑制 LD 形成可能是一种非常有效的方法，专门针对 GBM，且对细胞毒性很小正常脑组织中未检测到 LD。这项研究的完成将显着推进我们的对脂质代谢重编程的理解可能会带来对抗 GBM 的新方法。