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Abstract

The prognosis for intrahepatic cholangiocarcinoma (iCCA), a complex and aggressive form of primary liver cancer, is challenging due to factors such as advanced stage at diagnosis and a diverse genetic landscape. This complexity highlights the necessity of exploring and understanding the nuances of genetic mutations specific to iCCA and their potential as therapeutic targets. Gain-of-function mutations in Isocitrate dehydrogenase 1 (IDH1), leading to the production of the oncometabolite 2-hydroxyglutarate (2-HG), are particularly noteworthy in iCCA, where such mutations are common. IDH1, a key enzyme in the citric acid cycle catalyzing the oxidative decarboxylation of isocitrate to α-ketoglutarate, becomes a critical focus due to its altered role in iCCA. The detrimental effects of mutant IDH1 stem from its aberrant production of 2-HG, which competitively inhibits α-ketoglutarate-dependent oxygenases, thus affecting various biological processes including DNA and histone demethylation, hypoxic response, and collagen maturation, contributing significantly to tumorigenesis by altering epigenetic and cellular signaling pathways. To understand the role of IDH1 in iCCA and the implications of 2-HG, a tailored mouse model was employed, using hydrodynamic tail vein injection, which allowed for the direct introduction of genetic elements into the liver. The study shows that IDH1 mutations, in combination with other oncogenic events, significantly reduce the survival of tumor-bearing mice. The accumulation of 2-HG in tumors leads to enhanced methylation, a shift in tumor phenotype towards cholangiocytic characteristics, and changes in stromal cell infiltration. Through mass spectrometry of iCCA extracellular matrix, key elements of the 2-HG-driven phenotype were identified. This research provided extensive insights into the molecular and cellular effects of IDH1 mutations in iCCA, revealing their impact on glycosylation, liver cell differentiation, and tumor traits. A distinct aspect of this thesis was the investigation of immune and extracellular matrix dynamics in the context of 2-HG accumulation. This exploration highlighted the intricate relationship between immune cell infiltration, immune modulation, and IDH1 mutations, enhancing understanding of the tumor microenvironment in iCCA. Additionally, the study introduced alternative murine iCCA models and mimicked patient-specific genomic patterns, enriching the research spectrum. A significant breakthrough was the identification of a novel immunogenic peptide, targeting IDH1 mutant cholangiocarcinoma cells, paving the way for mutation-specific immunotherapy. In conclusion, this thesis demonstrates the critical role of mutant IDH1 in modulating the tumor microenvironment and cell differentiation in iCCA. It significantly advances our knowledge of iCCA pathology and lays the groundwork for innovative, targeted treatment strategies and personalized medicine.