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Mixed hepatocellular – cholangiocarcinoma derives from liver progenitor cells and depends on senescence and IL6 trans-signaling, single-cell RNA sequencing

ABSTRACT: Mixed hepatocellular – cholangiocarcinoma (HCC-CCA) is a highly malignant primary liver cancer of increasing incidence for which the cell of origin and molecular pathogenesis have not yet been fully elucidated. Here, by linking YFP to the progenitor cell specific promoter of Foxl1 in Mdr2-KO mice, we generated a lineage tracing mouse model for liver cancer to monitor the development of mixed HCC-CCA tumors following a prolonged period of liver inflammation. In this model of chronic hepatitis, we demonstrate that liver progenitor cells are the source of mixed HCC-CCA tumors but not of hepatocellular carcinoma (HCC). Moreover, we show that IL6, originating from senescent hepatic cells, is involved in progenitor cell proliferation and development of mixed HCC-CCA tumors via IL6 trans-signaling. These findings could form the basis for the development of novel therapeutic approaches for treatment of mixed HCC-CCA liver cancer.

ORGANISM(S): Mus musculus

PROVIDER: GSE202089 | GEO | 2023/11/15

REPOSITORIES: GEO

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Mixed hepatocellular – cholangiocarcinoma derives from liver progenitor cells and depends on senescence and IL6 trans-signaling, bulk RNA sequencing

Project description:Mixed hepatocellular – cholangiocarcinoma (HCC-CCA) is a highly malignant primary liver cancer of increasing incidence for which the cell of origin and molecular pathogenesis have not yet been fully elucidated. Here, by linking YFP to the progenitor cell specific promoter of Foxl1 in Mdr2-KO mice, we generated a lineage tracing mouse model for liver cancer to monitor the development of mixed HCC-CCA tumors following a prolonged period of liver inflammation. In this model of chronic hepatitis, we demonstrate that liver progenitor cells are the source of mixed HCC-CCA tumors but not of hepatocellular carcinoma (HCC). Moreover, we show that IL6, originating from senescent hepatic cells, is involved in progenitor cell proliferation and development of mixed HCC-CCA tumors via IL6 trans-signaling. These findings could form the basis for the development of novel therapeutic approaches for treatment of mixed HCC-CCA liver cancer.

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