Role of protein mediate fatty acid uptake in liver cancer

蛋白质介导脂肪酸摄取在肝癌中的作用

• 批准号: 10225385
• 负责人: Daniel Nomura
• 金额: $ 50.81万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-17 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10225385
• 关键词: Ablation; Aerobic; Attention; Biliary; Bioenergetics; Biological Assay; Biological Models; Blood Circulation; Cancer Biology; Carcinoma; Cell surface; Characteristics; Citric Acid Cycle; Data; Dependence; Development; Disease; Drug Targeting; Experimental Neoplasms; Fatty Acids; Fatty acid glycerol esters; Fatty-acid synthase; Genetic; Glucose; Glycolysis; Growth; Hepatic; Human; Incidence; Intrahepatic Cholangiocarcinoma; Isotopes; Lead; Light; Lipids; Liver; Malignant Neoplasms; Malignant neoplasm of liver; Mediating; Metabolic; Metabolism; Mitochondria; Modeling; Mus; Nonesterified Fatty Acids; Pathway interactions; Pharmacology; Physiological; Physiology; Primary Neoplasm; Primary carcinoma of the liver cells; Proteins; Proto-Oncogene Proteins c-akt; Pyruvate; Role; Sampling; Signal Transduction; Signaling Molecule; Source; System; Techniques; Testing; Tissues; Tumor Escape; Up-Regulation; base; biliary tract; cancer cell; combat; ex vivo respiration; fatty acid metabolism; genetic approach; imaging approach; in vivo; intrahepatic; lipid biosynthesis; lipid transport; lipidomics; long chain fatty acid; loss of function; membrane synthesis; metabolomics; mouse model; neoplastic cell; novel; oxidation; patient derived xenograft model; tumor; tumor growth; tumor metabolism; uptake

Project Summary While less frequent than hepatocellular carcinomas (HCC), intrahepatic carcinomas (ICC) are a lethal condition with rising incidence rate and, currently, few treatment options. We recently demonstrate that fatty acid synthase (FASN) activity is required for efficient growth of HCC but not for ICC. Given the essential role of fatty acids for membrane synthesis, signaling molecules, and energy substrates this led us to hypothesize that ICC relies on the uptake of exogenous free fatty acids (FFA). Importantly, cell surface molecules have been identified that that are required for efficient uptake of free fatty acids from the circulation. As these molecules have already been shown to be drugable targets, in principle, they might offer new treatment approaches for this deadly disease. Our central hypothesis that protein mediated fatty acid uptake is required for ICC growth in vivo to generate as yet unknown signals that cannot be provided via de novo synthesis of fatty acids. This hypothesis is supported by key preliminary data showing that ICC, but not HCC, express the classical hepatic fatty acid transporters Slc27a2 and Slc27a5 and that ICC isolated primary tumor cells display a robust uptake of exogenous fatty acids. Moreover, using novel assay to determine changes in fatty acid uptake during tumor growth in vivo, we were able to show higher exogenous long-chain fatty acid uptake by ICC tumors compared to an HCC model. Importantly, loss of Slc27a5 diminishes ICC growth in experimental tumor models in spite of FASN expression. Preliminary lipidomics studies comparing lipid compositions in normal and end-stage ICC and HCC models showed significantly higher fatty acid levels in ICC tumor laden livers compared to HCC and for some lipid species even surpassing concentrations found in normal liver. These studies also have begun to shed light on the metabolic fate of the exogenous fatty acids, which might lead to identification of key signals uniquely provided by exogenous fatty acids. Here, using mouse model systems and human ICC PDX, we will determine when and to what extend exogenous FFA uptake is required for the growth of ICC, how it is facilitated, and what unique roles Slc27 driven FFA uptake provides.

项目摘要 虽然比肝细胞癌（HCC）发生率低，但肝内癌（ICC）是一种致死性疾病 发病率不断上升，目前治疗选择很少。我们最近发现脂肪酸 肝细胞癌的有效生长需要纤维化合成酶（FGFAP）活性，但ICC不需要。考虑到脂肪的重要作用 细胞膜合成所需的酸、信号分子和能量底物，这使我们假设ICC 依赖于外源性游离脂肪酸（FFA）的摄取。重要的是，细胞表面分子已经被 确定了从循环中有效吸收游离脂肪酸所需的。当这些分子 已经被证明是可药物治疗的目标，原则上，它们可能会提供新的治疗方法， 这种致命的疾病。我们的中心假设是，ICC需要蛋白质介导的脂肪酸摄取 在体内生长，以产生尚未未知的信号，这些信号不能通过从头合成 脂肪酸这一假设得到了关键的初步数据的支持，这些数据表明，ICC而不是HCC表达了 经典的肝脂肪酸转运蛋白Slc27a2和Slc27a5以及ICC分离的原发性肿瘤细胞显示 对外源性脂肪酸的大量摄取。此外，使用新的测定方法来确定脂肪酸的变化， 在体内肿瘤生长过程中的摄取，我们能够显示更高的外源性长链脂肪酸摄取， ICC肿瘤与HCC模型的比较。重要的是，Slc27a5的缺失减少了实验性的ICC生长。 肿瘤模型中，尽管表达。初步脂质组学研究比较了 正常和终末期ICC和HCC模型显示，在ICC肿瘤负载中脂肪酸水平显著更高， 肝细胞癌相比，一些脂质种类甚至超过了正常肝脏中发现的浓度。 这些研究也开始阐明外源性脂肪酸的代谢命运， 导致鉴定由外源脂肪酸唯一提供的关键信号。在这里，使用小鼠模型 系统和人类ICC PDX，我们将确定何时以及在何种程度上需要外源性FFA摄取 对于ICC的增长，它是如何促进的，以及Slc27驱动FFA摄取提供了什么独特的作用。