Role of protein mediate fatty acid uptake in liver cancer

项目摘要 虽然比肝细胞癌少，但肝内癌是一种致命的疾病。 随着发病率的上升，目前几乎没有治疗选择。我们最近证明了脂肪酸 合酶(FASN)活性是肝细胞癌高效生长所必需的，而不是肝细胞癌生长所必需的。鉴于脂肪的基本作用 用于膜合成、信号分子和能量底物的酸，这导致我们假设ICC 依赖于外源游离脂肪酸(FFA)的吸收。重要的是，细胞表面分子已经 确定了有效地从循环中摄取游离脂肪酸所需的物质。因为这些分子 已经被证明是可用药的靶点，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不能通过从头合成提供的未知信号 脂肪酸。这一假说得到了关键的初步数据的支持，这些数据表明ICC而不是肝癌表达了 经典肝脏脂肪酸转运蛋白Slc27a2和Slc27a5及ICC分离的原代肿瘤细胞显示 对外源脂肪酸的强劲吸收。此外，使用新的分析方法来确定脂肪酸的变化 在体内肿瘤生长过程中，我们能够显示更高的外源性长链脂肪酸摄取率 ICC肿瘤与肝细胞癌模型的比较。重要的是，SLc27a5的缺失会减少实验性的ICC生长 肿瘤模型，尽管FASN表达。脂类组学初步研究比较了 正常和终末期ICC和肝细胞癌模型显示，ICC肿瘤中的脂肪酸水平显著升高 与肝细胞癌相比，一些脂质物种的浓度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，这可能会 导致识别由外源脂肪酸唯一提供的关键信号。这里，使用鼠标模型 系统和人类ICC PDX，我们将确定何时以及在多大程度上需要外源性FFA摄取 对于ICC的增长，它是如何促进的，以及SLC27驱动的FFA吸收提供了什么独特的作用。

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.