Plasticity of combined hepatocellular-cholangiocarcinoma

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Primary liver carcinomas include hepatocellular carcinoma, cholangiocellular carcinoma (CC) and mixed hepatocellular-cholangiocellular carcinoma (HCC-CC). Especially the latter type shows an increasing incidence. HCC-CC comprises a heterogeneous group of tumors that show areas of hepatocellular and cholangiocellular differentiation. The recent WHO classification differentiates HCC-CCs of classical type from those with stem-cell features. However, there is now evidence that stem-cell feature may be acquired during dedifferentiation of hepatocytes. In addition, lineage tracing experiments clearly showed that CC may develop from hepatocytes suggesting plasticity as the underlying mechanism.The current project aims at the identification of the mechanisms of hepatocellular plasticity. Therefore, differential genetic lesions and differentially expressed genes between tumor areas showing hepatocellular and cholangiocellular differentiation will be determined using genome-wide Next Generation Sequencing and RNA-Sequencing (RNAseq), respectively. Subsequently, the candidate genes will be tested directly in vivo using chimeric mosaic mouse models to evaluate their influence on the tumor phenotype and biology. This integrative approach (morphological differentiation, comprehensive definition of differentially altered candidates, and functional characterization in vivo) will identify the mechanisms of hepatocellular plasticity, will improve our knowledge on the pathogenesis of HCC-CC and reflects a new dimension for the identification of phenotypic drivers, which can be explored as therapeutic targets for the treatment of HCC-CC patients, whose prognosis is mainly determined by the cholangiocarcinoma component.