Plasticity of combined hepatocellular-cholangiocarcinoma

原发性肝癌包括肝细胞癌、胆管细胞癌（CC）和肝细胞-胆管细胞混合癌（HCC-CC）。特别是后一种类型的发病率越来越高。HCC-CC包括一组异质性肿瘤，显示肝细胞和胆管细胞分化区域。世卫组织最近的分类将经典型hcc与具有干细胞特征的hcc区分开来。然而，现在有证据表明，干细胞特征可能在肝细胞去分化过程中获得。此外，谱系追踪实验清楚地表明，CC可能从肝细胞发展而来，这表明可塑性是潜在的机制。目前的项目旨在确定肝细胞可塑性的机制。因此，将分别使用全基因组Next Generation Sequencing和RNA-Sequencing （RNAseq）来确定显示肝细胞和胆管细胞分化的肿瘤区域之间的差异遗传病变和差异表达基因。随后，候选基因将使用嵌合小鼠模型直接在体内进行测试，以评估其对肿瘤表型和生物学的影响。这种综合方法（形态学分化、差异改变候选细胞的综合定义和体内功能表征）将确定肝细胞可塑性的机制，将提高我们对HCC-CC发病机制的认识，并反映出鉴定表型驱动因素的新维度，可以作为HCC-CC患者治疗的治疗靶点进行探索。其预后主要由胆管癌成分决定。

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.