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 tumour 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 introduction of genetic elements directly into the liver. Our results revealed that IDH1 mutations combined with other iCCA-driving oncogenic events shorten 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 altered stromal cell infiltration (e.g. fibroblasts, lymphatics). Further, to identify key players contributing to 2-HG-driven phenotype, we apply mass spectrometry analyses of extracellular matrix from liver cancer tissue. Additionally, to target IDH1 mutant cholangiocarcinoma cells, we screened for peptides with an immunogenic capacity and identified a novel peptide, which is suitable for mutation-specific vaccination. Further experiments are now investigating the therapeutic potential of the novel peptide for rescuing IDH1-related iCCA.

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 immunotherapeutic options for targeting IDH1 as a tumor-specific neoantigen.

Publication History

Article published online:
20 January 2025