• A Corrigendum to this article was published on 21 January 2015
  • A Corrigendum to this article was published on 18 November 2015

Abstract

Mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 are among the most common genetic alterations in intrahepatic cholangiocarcinoma (IHCC), a deadly liver cancer1,2,3,4,5. 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 maturation6,7,8,9,10. 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 IHCCs4,5, 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.

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Gene Expression Omnibus

Data deposits

Affymetrix Mouse 420Av2 DNA microarray data have been deposited in the Gene Expression Omnibus under accession number GSE57002.

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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 We also thank S. Thorgeirsson and J. Andersen for sharing unpublished data sets.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 Contra el Cáncer (AECC).

Author information

Author notes

    • Supriya K. Saha
    •  & Christine A. Parachoniak

    These authors contributed equally to this work.

Affiliations

  1. Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts 02114, USA

    • Supriya K. Saha
    • , Christine A. Parachoniak
    • , Krishna S. Ghanta
    • , Julien Fitamant
    • , Kenneth N. Ross
    • , Mortada S. Najem
    • , Sushma Gurumurthy
    • , Vikram Deshpande
    • , Andrew X. Zhu
    • , Cristina R. Ferrone
    • , Sridhar Ramaswamy
    •  & Nabeel Bardeesy
  2. Department of Medical Oncology, Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA

    • Esra A. Akbay
    •  & Kwok-Kin Wong
  3. 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

    • Daniela Sia
    • , Helena Cornella
    •  & Josep M. Llovet
  4. Mount Sinai Liver Cancer Program, Division of Liver Diseases, Dept of Medicine. Icahn School of Medicine at Mount Sinai, New York 10029, USA

    • Daniela Sia
    • , Oriana Miltiadous
    •  & Josep M. Llovet
  5. Gastrointestinal Surgery and Liver Transplantation Unit, National Cancer Institute, and Department of Experimental Oncology, Milan 20133, Italy

    • Daniela Sia
  6. Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160, USA

    • Chad Walesky
    •  & Udayan Apte
  7. University of Rochester Medical Center, Rochester, New York 14642, USA

    • Aram F. Hezel
  8. Agios Pharmaceuticals, Cambridge, Massachusetts 02139, USA

    • Katharine E. Yen
    • , Kimberly S. Straley
    • , Jeremy Travins
    • , Janeta Popovici-Muller
    •  & Camelia Gliser
  9. Institució Catalana de Recerca i Estudis Avançats, Barcelona, Catalonia 08010, Spain

    • Josep M. Llovet
  10. University of Barcelona, Catalonia 08036, Spain

    • Josep M. Llovet
  11. Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA

    • Sridhar Ramaswamy

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Contributions

S.K.S. and C.A.P. contributed equally to the study. S.K.S., C.A.P., K.S.G., M.S.N. and S.G. carried out the experiments involving hepatoblasts and mouse models. K.N.R. and S.R. performed computational analysis on gene expression data. J.F. performed immunohistochemistry on tissue sections. E.A.A. and K.-K.W. assisted with the generation of the IDH mutant mice. V.D. analysed the histology from the murine liver specimens. C.W. and U.A. carried out the experiments involving the HNF-4α knockout mice. D.S., H.C., O.M. and J.M.L. performed GSEA analysis on human IHCC samples. A.X.Z., A.F.H. and C.R.F. were involved in the study design. K.E.Y., K.S.S., J.T., J.P.-M. and C.G. developed and provided the AGI-5027 compound and measured 2HG in our samples. S.K.S., C.A.P. and N.B. designed the experiments and wrote the paper. N.B. supervised the studies. All authors discussed the results and commented on the manuscript.

Competing interests

K.Y., K.S., J.T., J.P.-M. and C.G. are employees of Agios Pharmaceuticals.

Corresponding author

Correspondence to Nabeel Bardeesy.

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https://doi.org/10.1038/nature13441

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