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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

基本信息

批准号：
9978744
负责人：
Daniel Nomura
金额：
$ 51.03万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
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：
2018-08-17 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9978744
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 long chain fatty acid loss of function membrane synthesis metabolomics mouse model neoplastic cell novel oxidation tumor tumor growth tumor metabolism uptake

项目摘要

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.

项目概要虽然肝内癌 (ICC) 的发病率低于肝细胞癌 (HCC)，但它是一种致命疾病发病率不断上升，目前治疗选择很少。我们最近证明脂肪酸 HCC 的有效生长需要合酶 (FASN) 活性，但 ICC 则不需要。鉴于脂肪的重要作用膜合成、信号分子和能量底物的酸，这使我们推测 ICC 依赖于外源游离脂肪酸（FFA）的吸收。重要的是，细胞表面分子确定了从循环中有效吸收游离脂肪酸所必需的。由于这些分子已经被证明是可药物靶点，原则上，它们可能为以下疾病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体内生长产生迄今为止未知的信号，这些信号无法通过从头合成提供脂肪酸。这一假设得到了关键初步数据的支持，这些数据表明 ICC（而非 HCC）表达了经典肝脂肪酸转运蛋白 Slc27a2 和 Slc27a5 以及 ICC 分离的原发性肿瘤细胞显示的外源脂肪酸的强劲吸收。此外，使用新的测定法来确定脂肪酸的变化在体内肿瘤生长过程中的摄取，我们能够通过以下方法显示出更高的外源长链脂肪酸摄取： ICC 肿瘤与 HCC 模型的比较。重要的是，Slc27a5 的缺失会减少实验中 ICC 的生长尽管存在 FASN 表达，但肿瘤模型。比较脂质成分的初步脂质组学研究正常和终末期 ICC 和 HCC 模型在充满 ICC 肿瘤的情况下显示出显着较高的脂肪酸水平与 HCC 相比，肝脏中的某些脂质种类甚至超过了正常肝脏中的浓度。这些研究也开始揭示外源脂肪酸的代谢命运，这可能导致识别外源脂肪酸独特提供的关键信号。这里，使用鼠标模型系统和人类 ICC PDX，我们将确定何时以及需要何种程度的外源 FFA 摄取对于 ICC 的发展，如何促进它，以及 Slc27 驱动的 FFA 吸收提供了哪些独特的作用。