Dissecting the molecular interplay between tumor cells and –stroma in primary liver cancer

Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) constitute the two most prevalent types of primary liver cancer, together accounting for approximately 95 % of cases. In contrast to the desmoplastic appearance of most CCAs, the majority of HCCs usually appear as stroma-scant tumors. Still, cases with unusual phenotypes such as solid CCA and sclerotic HCC can be detected. However, the tumor microenvironment which consists of cancer-associated fibroblasts, endothelial cells, various types of immune cells, and other stroma elements may play a key role in cancer development, progression and may even contribute to the process of determining the cancer phenotype. On the basis of these observations, this project aims at elucidating the mechanism driving the tumor phenotype of primary liver cancer in order to identify novel therapeutic targets and eventually predictive biomarkers. For this purpose, each five informative samples of CCA and HCC with a stroma-poor or –rich phenotype, respectively, were selected for exome and transcriptome sequencing. Data integration revealed 29 genes potentially driving the tumor phenotype. To validate the loss-of-function candidates, two transposon-based mosaic mouse models were used (HCC model: MYC-AKT1 in wildtype C57BL/6 mice; iCCA model: KRASG12V in p19-/- mice). Transposon vectors together with the shRNA library (5 shRNAs/per candidate gene) were hydrodynamically injected into the tail vein of mice. Tumor development was monitored and all dissectible tumor nodules were individually evaluated by histological analysis. In the case of a switch in tumor phenotype (change of tumor type or alteration of tumor stroma), the expressed shRNA was identified by sequencing. Single gene validation and further mechanistic analyses are currently ongoing and the results will be presented during the meeting.

Publication History

Article published online:
04 January 2021