title: Differential requirement for de novo lipogenesis in cholangiocarcinoma and hepatocellular carcinoma of mice and humans.
abstract: Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) are the most prevalent types of primary liver cancer. These malignancies have limited treatment options, resulting in poor patient outcomes. Metabolism reprogramming, 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-coenzyme A and malonyl-coenzyme A. Increased FASN expression has been reported in multiple tumor types, and inhibition of FASN expression has been shown to have tumor-suppressing activity. Intriguingly, we found that while FASN is up-regulated in human HCC samples, its expression is frequently low in human ICC specimens. Similar results were observed in mouse ICC models induced by different oncogenes. Ablating FASN in the mouse liver did not affect activated AKT and Notch (AKT/Notch intracellular domain 1) induced ICC formation in vivo. Furthermore, while both HCC and ICC lesions develop in mice following hydrodynamic injection of AKT and neuroblastoma Ras viral oncogene homolog oncogenes (AKT/Ras), deletion of FASN in AKT/Ras mice triggered the development almost exclusively of ICCs. In the absence of FASN, ICC cells might receive lipids for membrane synthesis through exogenous fatty acid uptake. In accordance with the latter hypothesis, ICC cells displayed high expression of fatty acid uptake-related proteins and robust long-chain fatty acid uptake.
  
  
  
  Our data demonstrate that FASN dependence is not a universal feature of liver tumors: while HCC development is highly dependent of FASN and its mediated lipogenesis, ICC tumorigenesis can be insensitive to FASN deprivation; our study supports novel therapeutic approaches to treat this pernicious tumor type with the inhibition of exogenous fatty acid uptake. (Hepatology 2016;63:1900-1913).
authors.affiliation: School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.|Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA.
authors.forename: Lei
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA.|Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China.
authors.forename: Li
authors.initials: L
authors.lastname: Che
authors.affiliation: Department of Nutritional Sciences and Toxicology, University of California-Berkeley, Berkeley, CA.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Tharp
authors.affiliation: Department of Nutritional Sciences and Toxicology, University of California-Berkeley, Berkeley, CA.
authors.forename: Hyo-Min
authors.initials: HM
authors.lastname: Park
authors.affiliation: Department of Clinical and Experimental Medicine, University of Sassari, Sassari, Italy.
authors.forename: Maria G
authors.initials: MG
authors.lastname: Pilo
authors.affiliation: Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA.|Department of Medical Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Cao
authors.affiliation: Institute of Pathology, University of Greifswald, Greifswald, Germany.
authors.forename: Antonio
authors.initials: A
authors.lastname: Cigliano
authors.affiliation: Department of Clinical and Experimental Medicine, University of Sassari, Sassari, Italy.
authors.forename: Gavinella
authors.initials: G
authors.lastname: Latte
authors.affiliation: Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA.|Department of Gastroenterology, Guizhou Provincial People's Hospital, The Affiliated People's Hospital of Guizhou Medical University, Guiyang, Guizhou Province, China.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Institute of Pathology, University of Greifswald, Greifswald, Germany.
authors.forename: Silvia
authors.initials: S
authors.lastname: Ribback
authors.affiliation: Institute of Pathology, University of Greifswald, Greifswald, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Dombrowski
authors.affiliation: Institute of Pathology, University of Greifswald, Greifswald, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Evert
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Gores
authors.affiliation: Department of Nutritional Sciences and Toxicology, University of California-Berkeley, Berkeley, CA.
authors.forename: Andreas
authors.initials: A
authors.lastname: Stahl
authors.affiliation: Department of Clinical and Experimental Medicine, University of Sassari, Sassari, Italy.
authors.forename: Diego F
authors.initials: DF
authors.lastname: Calvisi
authors.affiliation: Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA.
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
mesh_terms: D000818:Animals; D001650:Bile Duct Neoplasms / Q000378:metabolism*; D018955:CD36 Antigens / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D045744:Cell Line, Tumor; D018281:Cholangiocarcinoma / Q000378:metabolism*; D064429:Fatty Acid Synthases / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D050155:Lipogenesis; D008113:Liver Neoplasms / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051057:Proto-Oncogene Proteins c-akt; D018631:ras Proteins
chemical_list: D018955:CD36 Antigens; D005227:Fatty Acids; D064429:Fatty Acid Synthases; D051057:Proto-Oncogene Proteins c-akt; D018631:ras Proteins