The role of IDH mutation in liver cell plasticity and cancer

The application of next generation sequencing to bile duct cancers (cholangiocarcinoma) has revealed a subgroup with mutations in the Isocitrate Dehydrogenase (IDH1, IDH2) genes, which appear non-overlapping with other drivers including TP53 and KRAS and which are associated with relatively favourable, but still poor, clinical prognosis.

IDH1/2 mutations result in neomorphic production of the oncometabolite 2-hydroxyglutarate (2HG), which causes cell toxicity, DNA hypermethylation, and repression of cellular differentiation. This project tests two hypotheses.

First, it seeks to determine whether 2HG production can metabolically reprogramme liver cell identity, triggering a cell fate change from a hepatocyte to a biliary phenotype, thereby promoting the formation of cholangiocarcinoma.

I will seek to define the cell populations in the liver in which IDH1 mutations occur in disease and use lineage tracing techniques to establish whether IDH1 mutation results in an increase in hepatic progenitor or ductal cells in vivo, as well as which cell types give rise to these ductular reactions.

Second, I shall examine whether 2HG causes non-cell-autonomous local toxicity or inflammation, and determine whether this contributes to tumorigenesis.

My results will elucidate fundamental mechanisms of biliary carcinogenesis and suggest the likely efficacy of targeted 2HG inhibition or, indeed, 2HG overexpression.