Mutant IDH inhibits HNF-4α to block hepatocyte differentiation and promote biliary cancer

Supriya K. Saha, Christine A. Parachoniak, Krishna S. Ghanta, Julien Fitamant, Kenneth N. Ross, Mortada S. Najem, Sushma Gurumurthy, Esra A. Akbay, Daniela Sia, Helena Cornella, Oriana Miltiadous, Chad Walesky, Vikram Deshpande, Andrew X. Zhu, Aram F. Heze, Katharine E. Yen, Kimberly S. Straley, Jeremy Travins, Janeta Popovici-Muller, Camelia GliserCristina R. Ferrone, Udayan Apte, Josep M. Llovet, Kwok Kin Wong, Sridhar Ramaswamy, Nabeel Bardeesy

Research output: Contribution to journalArticlepeer-review

210 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)110-152
Number of pages43
JournalNature
Volume513
Issue number7516
DOIs
StatePublished - Sep 2014

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'Mutant IDH inhibits HNF-4α to block hepatocyte differentiation and promote biliary cancer'. Together they form a unique fingerprint.

Cite this