Fatty acid transporters in cholangiocarcinoma pathogenesis

描述(申请人提供)：肝内胆管细胞癌(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是一种致命的疾病，几乎没有治疗选择。ICC显然代表了一种没有得到满足的医疗需求的癌症，因为NIH资助的ICC研究非常有限，而且FDA也没有批准针对ICC的靶向治疗。长期以来，脂类代谢异常一直被认为是癌症发生过程中的一个重要代谢事件。然而，几乎所有的研究都只集中于增加新生脂肪生成，作为肿瘤细胞生长所需脂肪酸的来源。外源脂肪酸的作用在很大程度上被忽视了。最近，我们发现在人类ICC样本中，从头脂肪酸合成途径基因表达下调，AKT和Notch癌基因(AKT/NICD)的激活不需要从头脂肪生成来诱导小鼠ICC的发生。结果提示，ICCs在细胞生长过程中可能依赖于脂肪酸的摄取来形成脂肪。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体，包括FATP1、FATP2和FATP5；而人ICC细胞在脂蛋白缺乏的条件下无法生长。基于这些观察结果，我们推测FATP1、FATP2和FATP5是人ICC细胞生长和AKT/NICD诱导小鼠ICC发病所必需的。这一假设将在两个目标上被击败。在目标1中，我们将确定ICC细胞在体外生长所需的FATP。在目标2中，我们将确定AKT/NICD诱导的小鼠ICC形成所需的FATP。这项申请代表了加州大学旧金山分校的肝癌研究专家陈欣博士和加州大学伯克利分校的脂肪酸转运体和肝脏疾病专家安德烈亚斯·斯塔尔博士的协同效应。这项研究将揭示在肿瘤发展过程中一个以前被忽视的脂肪酸代谢领域。这项研究将阐明脂肪酸摄取和可能的肥胖如何促进肿瘤的发生；因此，为导致肿瘤启动和进展的分子事件提供了新的机制洞察。这一结果也可能为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.