TY - JOUR
T1 - Mutant IDH inhibits HNF-4α to block hepatocyte differentiation and promote biliary cancer
AU - Saha, Supriya K.
AU - Parachoniak, Christine A.
AU - Ghanta, Krishna S.
AU - Fitamant, Julien
AU - Ross, Kenneth N.
AU - Najem, Mortada S.
AU - Gurumurthy, Sushma
AU - Akbay, Esra A.
AU - Sia, Daniela
AU - Cornella, Helena
AU - Miltiadous, Oriana
AU - Walesky, Chad
AU - Deshpande, Vikram
AU - Zhu, Andrew X.
AU - Heze, Aram F.
AU - Yen, Katharine E.
AU - Straley, Kimberly S.
AU - Travins, Jeremy
AU - Popovici-Muller, Janeta
AU - Gliser, Camelia
AU - Ferrone, Cristina R.
AU - Apte, Udayan
AU - Llovet, Josep M.
AU - Wong, Kwok Kin
AU - Ramaswamy, Sridhar
AU - Bardeesy, Nabeel
N1 - Funding Information:
Acknowledgements We thank R. Mostoslavsky, L. Ellisen, A. Kimmelman, and members of the Bardeesy laboratory for valuable input. We also thank S. Thorgeirsson and J. Andersen for sharing unpublished data sets. This work was supported by grants from TargetCancer Foundation and the National Institutes of Health (R01CA136567-02 and P50CA1270003) to N.B. N.B. holds the Gallagher Endowed Chair in Gastrointestinal Cancer Research at Massachusetts General Hospital. S.K.S. is the recipient of a Cholangiocarcinoma Foundation/Conquer Cancer Foundation of ASCO Young Investigator Award, and an American Cancer Society Postdoctoral Fellowship (PF-13-294-01-TBG). C.A.P. is the recipient of a Canadian Institutes of Health Research postdoctoral fellowship. N.B., J.M.L. and D.S are members of the Samuel Waxman Cancer Research Foundation Institute Without Walls. J.M.L. and D.S. are supported by the Asociación Española para el Estudio del Cáncer.
PY - 2014/9
Y1 - 2014/9
N2 - Mutations inisocitrate dehydrogenase 1 (IDH1) andIDH2 areamong the most common genetic alterations in intrahepatic cholangiocarcinoma (IHCC), a deadly liver cancer1-5. Mutant IDH proteins in IHCCand othermalignancies acquire an abnormal enzymatic activity allowing themto convert a-ketoglutarate (aKG) to 2-hydroxyglutarate (2HG), which inhibits the activity ofmultiple aKG-dependent dioxygenases, and results in alterations in cell differentiation, survival, and extracellularmatrixmaturation6-10.However, the molecular pathways by which IDH mutations lead to tumour formation remain unclear.HereweshowthatmutantIDHblocks liver progenitor cells from undergoing hepatocyte differentiation through the production of 2HG and suppression of HNF-4a, a master regulator of hepatocyte identityandquiescence.Correspondingly, genetically engineeredmousemodels expressingmutant IDHin the adult liver show an aberrant response to hepatic injury, characterized by HNF-4a silencing, impaired hepatocyte differentiation, andmarkedly elevated levels of cell proliferation. Moreover,IDH and Kras mutations, genetic alterations that co-exist in a subset of human IHCCs4,5, cooperate to drive the expansion of liver progenitor cells, development of premalignant biliary lesions, and progression tometastaticIHCC. These studies provide a functional link between IDHmutations, hepatic cell fate, and IHCC pathogenesis, and present a novel genetically engineered mouse model of IDH-driven malignancy.
AB - Mutations inisocitrate dehydrogenase 1 (IDH1) andIDH2 areamong the most common genetic alterations in intrahepatic cholangiocarcinoma (IHCC), a deadly liver cancer1-5. Mutant IDH proteins in IHCCand othermalignancies acquire an abnormal enzymatic activity allowing themto convert a-ketoglutarate (aKG) to 2-hydroxyglutarate (2HG), which inhibits the activity ofmultiple aKG-dependent dioxygenases, and results in alterations in cell differentiation, survival, and extracellularmatrixmaturation6-10.However, the molecular pathways by which IDH mutations lead to tumour formation remain unclear.HereweshowthatmutantIDHblocks liver progenitor cells from undergoing hepatocyte differentiation through the production of 2HG and suppression of HNF-4a, a master regulator of hepatocyte identityandquiescence.Correspondingly, genetically engineeredmousemodels expressingmutant IDHin the adult liver show an aberrant response to hepatic injury, characterized by HNF-4a silencing, impaired hepatocyte differentiation, andmarkedly elevated levels of cell proliferation. Moreover,IDH and Kras mutations, genetic alterations that co-exist in a subset of human IHCCs4,5, cooperate to drive the expansion of liver progenitor cells, development of premalignant biliary lesions, and progression tometastaticIHCC. These studies provide a functional link between IDHmutations, hepatic cell fate, and IHCC pathogenesis, and present a novel genetically engineered mouse model of IDH-driven malignancy.
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U2 - 10.1038/nature13441
DO - 10.1038/nature13441
M3 - Article
C2 - 25043045
AN - SCOPUS:84907033777
VL - 513
SP - 110
EP - 152
JO - Nature
JF - Nature
SN - 0028-0836
IS - 7516
ER -