Abstract 1880: Role of fatty acid synthase and do novo lipogenesis in liver cancer development in mice.

Abstract Aberrant metabolism, including increased de novo lipogenesis, is one of the hallmarks of cancer. Fatty Acid Synthase (Fasn) catalyzes the de novo synthesis of long-chain fatty acids from acetyl-CoA and malonyl-CoA. Increased Fasn expression has been reported in multiple tumor types, and inhibition of Fasn expression has been shown to have tumor-suppressing activity. However, how increased de novo lipogenesis contributes to tumor initiation and progression, especially in vivo, remains unknown. In our previous studies, we showed that overexpression of the activated form of AKT (myr-AKT) induced de novo lipogenesis, hepatocyte proliferation and, eventually, liver cancer formation in mice. The tumorigenesis process could be significantly accelerated via co-expression of activated form of Ras. In the AKTRas tumor model, tumors were predominantly (>80%) hepatocellular carcinoma (HCC), and the remaining (<20%) were intrahepatic cholangiocarcinoma (ICC). The ICCs were induced via hepatocyte-biliary epithelial cell metaplasia in a Notch dependent manner. Intriguingly, fat droplet formation, increased expression of Fasn and other lipogenesis pathway genes were identified in HCC lesions, but not ICC lesions. To define whether Fasn-mediated de novo lipogenesis is a key metabolic event downstream of mTORC1 during AKTRas-induced hepatocarcinogenesis, we utilized Fasn flox/flox mice, and co-expressed AKTRas in the Fasn KO hepatocytes. Of note, we found that ablation of Fasn completely inhibited AKT induced lipogenesis and hepatocyte proliferation in mice. However, loss of Fasn modestly delayed AKTRas-induced liver tumor development. Histological analysis revealed that these tumor lesions were predominantly ICCs. The ICC cells were highly proliferative, and did not express Fasn or any other lipogenic pathway gene. The results suggest that Fasn-mediated de novo lipogenesis is required for AKTRas-induced HCC formation, but this process is dispensable for ICC formation. In summary, our experiments support a critical role for Fasn as a downstream effector of mTORC1 in HCC pathogenesis. However, Fasn-mediated do novo fatty acid synthesis is not required in all tumor types. It is likely that other sources of fatty acids, presumably including those derived from the diet, can be utilized by cancer cells for membrane synthesis during cell proliferation. Citation Format: Xin Chen, Lei Li, Chunmei Wang, Matthias Evert, Diego F. Calvisi, Clay F. Semenkovich. Role of fatty acid synthase and do novo lipogenesis in liver cancer development in mice. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1880. doi:10.1158/1538-7445.AM2013-1880 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.