From genotype to phenotype: how IDH1 mutations alter the landscape of intrahepatic cholangiocarcinoma

Gain-of-function mutations in IDH1 render it with a neomorphic activity to produce an oncometabolite, 2-hydroxyglutarate (2-HG). Little is known about the relevance of this phenomenon in intrahepatic cholangiocarcinoma (iCCA), even though this gene is among the most frequently mutated genes in this tumor type. Furthermore, mutated IDH1 could serve as an important potential target for exploring novel therapeutic options for iCCA.

To elucidate the role of IDH1 in the development of iCCA and determine the functional consequences of 2-HG production, we employed a mouse model which enables the introduction of genetic elements directly into the liver. Our results revealed that IDH1 mutations combined with other iCCA-driving oncogenic events shorten the survival span of tumor-bearing mice. Moreover, 2-HG accumulation in tumor tissue leads not only to upregulation of methylation and induction of tumor differentiation but also to an altered abundance of stromal and immune cells in the tumor microenvironment. Further, to identify key players contributing to 2-HG-driven phenotype, we apply mass spectrometry analyses of the extracellular matrix from liver cancer tissue.

In summary, our results reveal a crucial role of IDH1 in shaping the tumor microenvironment and cell differentiation in iCCA and provide novel insights into key elements that contribute to the 2-HG-driven phenotype, providing direction for future therapeutic development in the context of IDH1-mutant iCCA.

Publication History

Article published online:
23 January 2024