Fatty acid transporters in cholangiocarcinoma pathogenesis

描述（申请人提供）：肝内胆管癌（ICC）是一种相对罕见的肝癌。然而，在过去的几十年里，ICC在美国的发病率一直在上升。ICC是一种几乎没有治疗选择的致命疾病。ICC显然代表了一种医疗需求未得到满足的癌症类型，因为NIH资助的ICC研究非常有限，FDA也没有批准针对ICC的靶向治疗。脂质代谢异常一直被认为是癌症发展过程中的主要代谢事件。然而，几乎所有的研究都只关注肿瘤细胞生长所需脂肪酸的来源，即脂肪从头生成的增加。外源性脂肪酸的作用在很大程度上被忽视了。最近，我们发现在人ICC样本中，从头开始的脂肪酸合成途径基因被下调，并且激活的AKT和Notch癌基因（AKT/NICD）诱导的小鼠ICC发育不需要从头开始的脂肪生成。结果表明，细胞生长过程中脂质形成可能依赖于脂肪酸的摄取。事实上，我们的初步研究表明，人和小鼠ICC细胞表达脂肪酸摄取转运蛋白，包括FATP1、FATP2和FATP5；而人ICC细胞在缺乏脂蛋白的培养基中不能生长。基于这些观察结果，我们假设FATP1， FATP2和FATP5是人类ICC细胞生长和AKT/NICD诱导小鼠ICC发病所必需的。这一假设将在两个方面得到验证。在目的1中，我们将确定体外ICC细胞生长所需的FATPs。在目标2中，我们将确定AKT/NICD诱导小鼠ICC形成所需的FATPs。该应用代表了UCSF肝癌研究专家陈鑫博士的协同效应；加州大学伯克利分校的Andreas Stahl博士是脂肪酸转运体和肝脏疾病方面的专家。这项研究将揭示一个以前被忽视的脂肪酸代谢在肿瘤发展中的领域。这项研究将揭示脂肪酸摄取和肥胖如何导致肿瘤的发生；因此，为导致肿瘤发生和发展的分子事件提供了新的机制见解。研究结果也可能为ICC的预防和治疗提供新的策略。

DESCRIPTION (provided by applicant): Intrahepatic Cholangiocarcinoma (ICC) is a relatively rare form of liver cancer. However, in the past decades the incidence of ICC has been increasing in the US. ICC is a deadly disease with few treatment options. ICC clearly represents a type of cancer with unmet medical need as there is very limited NIH funded research on ICC and there is no FDA approved targeted therapy for ICC. Aberrant lipid metabolism has long been recognized as a major metabolic event during cancer development. However, virtually all the studies have been focused solely on the increased de novo lipogenesis as the source for fatty acids required for tumor cell growth. The role of exogenous fatty acids has been largely ignored. Recently, we discovered that de novo fatty acid synthesis pathway genes are downregulated in human ICC samples, and de novo lipogenesis is not required for activated AKT and Notch oncogenes (AKT/NICD) induced ICC development in mice. The results suggest that ICCs may depend on fatty acid uptake for the lipid formation during cell growth. Indeed our preliminary studies showed that human and mouse ICC cells express fatty acid uptake transporters, including FATP1, FATP2 and FATP5; and human ICC cells fail to grow in lipoprotein deficient medium. Based on these observations, we hypothesize that FATP1, FATP2 and FATP5 are required for human ICC cell growth and AKT/NICD induced ICC pathogenesis in mice. The hypothesis will be bested in 2 aims. In aim 1, we will determine the FATPs which are required for ICC cell growth in vitro. And in aim 2, we will determine the FATPs which are required for AKT/NICD induced ICC formation in mice. This application represents the synergistic effects by Dr. Xin Chen of UCSF, an expert in liver cancer research; and Dr. Andreas Stahl of UC Berkeley, an expert in Fatty acid transporters and liver diseases. The study will uncover a previously ignored area of fatty acid metabolism in tumor development. The study will shed light into how fatty acid uptake and possibly obesity contributes to tumorigenesis; therefore provide novel mechanistic insight into the molecular events leading to tumor initiation and progression. The results will also likely provide novel strategy for ICC prevention and treatment.