title: Mutant IDH inhibits HNF-4α to block hepatocyte differentiation and promote biliary cancer.
abstract: Mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 are among the most common genetic alterations in intrahepatic cholangiocarcinoma (IHCC), a deadly liver cancer. Mutant IDH proteins in IHCC and other malignancies acquire an abnormal enzymatic activity allowing them to convert α-ketoglutarate (αKG) to 2-hydroxyglutarate (2HG), which inhibits the activity of multiple αKG-dependent dioxygenases, and results in alterations in cell differentiation, survival, and extracellular matrix maturation. However, the molecular pathways by which IDH mutations lead to tumour formation remain unclear. Here we show that mutant IDH blocks liver progenitor cells from undergoing hepatocyte differentiation through the production of 2HG and suppression of HNF-4α, a master regulator of hepatocyte identity and quiescence. Correspondingly, genetically engineered mouse models expressing mutant IDH in the adult liver show an aberrant response to hepatic injury, characterized by HNF-4α silencing, impaired hepatocyte differentiation, and markedly elevated levels of cell proliferation. Moreover, IDH and Kras mutations, genetic alterations that co-exist in a subset of human IHCCs, cooperate to drive the expansion of liver progenitor cells, development of premalignant biliary lesions, and progression to metastatic IHCC. These studies provide a functional link between IDH mutations, hepatic cell fate, and IHCC pathogenesis, and present a novel genetically engineered mouse model of IDH-driven malignancy.
authors.affiliation: 1] Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts 02114, USA [2].
authors.forename: Supriya K
authors.initials: SK
authors.lastname: Saha
authors.affiliation: 1] Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts 02114, USA [2].
authors.forename: Christine A
authors.initials: CA
authors.lastname: Parachoniak
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts 02114, USA.
authors.forename: Krishna S
authors.initials: KS
authors.lastname: Ghanta
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts 02114, USA.
authors.forename: Julien
authors.initials: J
authors.lastname: Fitamant
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts 02114, USA.
authors.forename: Kenneth N
authors.initials: KN
authors.lastname: Ross
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts 02114, USA.
authors.forename: Mortada S
authors.initials: MS
authors.lastname: Najem
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts 02114, USA.
authors.forename: Sushma
authors.initials: S
authors.lastname: Gurumurthy
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Esra A
authors.initials: EA
authors.lastname: Akbay
authors.affiliation: 1] HCC Translational Research Laboratory, Barcelona-Clínic Liver Cancer Group, Liver Unit, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, University of Barcelona, Catalonia 08036, Spain [2] Mount Sinai Liver Cancer Program, Division of Liver Diseases, Dept of Medicine. Icahn School of Medicine at Mount Sinai, New York 10029, USA [3] Gastrointestinal Surgery and Liver Transplantation Unit, National Cancer Institute, and Department of Experimental Oncology, Milan 20133, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Sia
authors.affiliation: HCC Translational Research Laboratory, Barcelona-Clínic Liver Cancer Group, Liver Unit, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, University of Barcelona, Catalonia 08036, Spain.
authors.forename: Helena
authors.initials: H
authors.lastname: Cornella
authors.affiliation: Mount Sinai Liver Cancer Program, Division of Liver Diseases, Dept of Medicine. Icahn School of Medicine at Mount Sinai, New York 10029, USA.
authors.forename: Oriana
authors.initials: O
authors.lastname: Miltiadous
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160, USA.
authors.forename: Chad
authors.initials: C
authors.lastname: Walesky
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts 02114, USA.
authors.forename: Vikram
authors.initials: V
authors.lastname: Deshpande
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts 02114, USA.
authors.forename: Andrew X
authors.initials: AX
authors.lastname: Zhu
authors.affiliation: University of Rochester Medical Center, Rochester, New York 14642, USA.
authors.forename: Aram F
authors.initials: AF
authors.lastname: Hezel
authors.affiliation: Agios Pharmaceuticals, Cambridge, Massachusetts 02139, USA.
authors.forename: Katharine E
authors.initials: KE
authors.lastname: Yen
authors.affiliation: Agios Pharmaceuticals, Cambridge, Massachusetts 02139, USA.
authors.forename: Kimberly S
authors.initials: KS
authors.lastname: Straley
authors.affiliation: Agios Pharmaceuticals, Cambridge, Massachusetts 02139, USA.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Travins
authors.affiliation: Agios Pharmaceuticals, Cambridge, Massachusetts 02139, USA.
authors.forename: Janeta
authors.initials: J
authors.lastname: Popovici-Muller
authors.affiliation: Agios Pharmaceuticals, Cambridge, Massachusetts 02139, USA.
authors.forename: Camelia
authors.initials: C
authors.lastname: Gliser
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts 02114, USA.
authors.forename: Cristina R
authors.initials: CR
authors.lastname: Ferrone
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160, USA.
authors.forename: Udayan
authors.initials: U
authors.lastname: Apte
authors.affiliation: 1] HCC Translational Research Laboratory, Barcelona-Clínic Liver Cancer Group, Liver Unit, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, University of Barcelona, Catalonia 08036, Spain [2] Mount Sinai Liver Cancer Program, Division of Liver Diseases, Dept of Medicine. Icahn School of Medicine at Mount Sinai, New York 10029, USA [3] Institució Catalana de Recerca i Estudis Avançats, Barcelona, Catalonia 08010, Spain [4] University of Barcelona, Catalonia 08036, Spain.
authors.forename: Josep M
authors.initials: JM
authors.lastname: Llovet
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Kwok-Kin
authors.initials: KK
authors.lastname: Wong
authors.affiliation: 1] Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts 02114, USA [2] Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.
authors.forename: Sridhar
authors.initials: S
authors.lastname: Ramaswamy
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts 02114, USA.
authors.forename: Nabeel
authors.initials: N
authors.lastname: Bardeesy
mesh_terms: D000818:Animals; D001650:Bile Duct Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D001653:Bile Ducts, Intrahepatic / Q000201:enzymology / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics*; D002455:Cell Division / Q000235:genetics; D019070:Cell Lineage / Q000235:genetics; D018281:Cholangiocarcinoma / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D004195:Disease Models, Animal; D005260:Female; D005977:Glutarates / Q000378:metabolism; D051557:Hepatocyte Nuclear Factor 4 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D022781:Hepatocytes / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D009362:Neoplasm Metastasis; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D013234:Stem Cells / Q000473:pathology; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D005977:Glutarates; C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4; C117307:KRAS protein, human; D050505:Mutant Proteins; D011518:Proto-Oncogene Proteins; C019417:alpha-hydroxyglutarate; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins