{
  "abstract": "Background RAS mutations are frequently observed in human cholangiocarcinoma (CCA), while they are relatively rare in hepatocellular carcinoma (HCC). The role of RAS-dependent signalling pathways in CCA development is currently not well understood.Objective The objective of this study was to investigate RAS-dependent signalling pathways in CCA and their role in tumour development and differentiation.Design We used genetically engineered mouse models with liver-specific deletion of tumour suppressors Rb and p53 together with activation of oncogenic Kras to investigate the cell of origin in intrahepatic CCA and to elucidate the role of RAS-dependent signalling pathways in CCA development.Results In mice, Kras-mutant intrahepatic CCA develops primarily from hepatocytes and shows activation of PI3K/AKT and MEK/ERK signalling downstream of KRAS. Targeted genetic inactivation of each of these pathways leads to delayed tumour growth and profound alterations in tumour differentiation. Specifically, reduced PI3K/AKT signalling promotes more well-differentiated tumours, whereas the inactivation of MEK/ERK signalling induces a differentiation switch towards a more hepatocyte-like phenotype. This switch is accompanied by activation of WNT/β-catenin signalling, a pathway commonly activated in human HCC.Conclusions These findings provide insights into the role of RAS-dependent pathways in liver cancer differentiation and offer a compelling explanation for the high prevalence of RAS mutations in human CCA compared with HCC.",
  "authors": [
    {
      "affiliations": [
        "TUM School of Medicine and Health, Department for Internal Medicine II, Technical University of Munich, TUM University Hospital, Munich, Germany",
        "Department of Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg, Heidelberg, Germany"
      ],
      "name": "Thomas Rösner"
    },
    {
      "affiliations": [
        "TUM School of Medicine and Health, Department for Internal Medicine II, Technical University of Munich, TUM University Hospital, Munich, Germany"
      ],
      "name": "Carina Rupp"
    },
    {
      "affiliations": [
        "TUM School of Medicine and Health, Department for Internal Medicine II, Technical University of Munich, TUM University Hospital, Munich, Germany"
      ],
      "name": "Christian Lechler"
    },
    {
      "affiliations": [
        "TUM School of Medicine and Health, Department for Internal Medicine II, Technical University of Munich, TUM University Hospital, Munich, Germany"
      ],
      "name": "Ulrike Bauer"
    },
    {
      "affiliations": [
        "TUM School of Medicine and Health, Department for Internal Medicine II, Technical University of Munich, TUM University Hospital, Munich, Germany"
      ],
      "name": "Saumya Sukumary Manmadhan"
    },
    {
      "affiliations": [
        "TUM School of Medicine and Health, Department for Internal Medicine II, Technical University of Munich, TUM University Hospital, Munich, Germany"
      ],
      "name": "Sophia Bernatik"
    },
    {
      "affiliations": [
        "TUM School of Medicine and Health, Department for Internal Medicine II, Technical University of Munich, TUM University Hospital, Munich, Germany"
      ],
      "name": "Fabian Delugré"
    },
    {
      "affiliations": [
        "TUM School of Medicine and Health, Department for Internal Medicine II, Technical University of Munich, TUM University Hospital, Munich, Germany"
      ],
      "name": "Franziska Ihli"
    },
    {
      "affiliations": [
        "TUM School of Medicine and Health, Department for Internal Medicine II, Technical University of Munich, TUM University Hospital, Munich, Germany"
      ],
      "name": "Tanja Derowski"
    },
    {
      "affiliations": [
        "TUM School of Medicine and Health, Department for Internal Medicine II, Technical University of Munich, TUM University Hospital, Munich, Germany"
      ],
      "name": "Simone Jörs"
    },
    {
      "affiliations": [
        "TUM School of Medicine and Health, Department for Internal Medicine II, Technical University of Munich, TUM University Hospital, Munich, Germany"
      ],
      "name": "Birgit Kohnke-Ertel"
    },
    {
      "affiliations": [
        "TUM School of Medicine and Health, Department for Internal Medicine II, Technical University of Munich, TUM University Hospital, Munich, Germany"
      ],
      "name": "Henrik Einwächter"
    },
    {
      "affiliations": [
        "TUM School of Medicine and Health, Institute of Pathology, Technical University of Munich, Munich, Germany",
        "TUM School of Medicine and Health, Comparative Experimental Pathology, Technical University of Munich, Munich, Germany",
        "German Cancer Consortium (DKTK), partner site Munich, a partnership between DKFZ and TUM University Hospital, Munich, Germany"
      ],
      "name": "Nicole Pfarr"
    },
    {
      "affiliations": [
        "TUM School of Medicine and Health, Institute of Pathology, Technical University of Munich, Munich, Germany",
        "TUM School of Medicine and Health, Comparative Experimental Pathology, Technical University of Munich, Munich, Germany",
        "German Cancer Consortium (DKTK), partner site Munich, a partnership between DKFZ and TUM University Hospital, Munich, Germany",
        "Bavarian Cancer Research Center (BZKF), Munich, Germany"
      ],
      "name": "Katja Steiger"
    },
    {
      "affiliations": [
        "TUM School of Medicine and Health, Institute of Pathology, Technical University of Munich, Munich, Germany",
        "TUM School of Medicine and Health, Comparative Experimental Pathology, Technical University of Munich, Munich, Germany",
        "German Cancer Consortium (DKTK), partner site Munich, a partnership between DKFZ and TUM University Hospital, Munich, Germany",
        "Bavarian Cancer Research Center (BZKF), Munich, Germany"
      ],
      "name": "Carolin Mogler"
    },
    {
      "affiliations": [
        "TUM School of Medicine and Health, Department for Internal Medicine II, Technical University of Munich, TUM University Hospital, Munich, Germany",
        "German Cancer Consortium (DKTK), partner site Munich, a partnership between DKFZ and TUM University Hospital, Munich, Germany",
        "Bavarian Cancer Research Center (BZKF), Munich, Germany",
        "Center for Protein Assemblies (CPA), Technical University of Munich, Garching, Germany",
        "Center for Organoid Systems (COS), Technical University of Munich, Garching, Germany"
      ],
      "name": "Maximilian Reichert"
    },
    {
      "affiliations": [
        "TUM School of Medicine and Health, Department for Internal Medicine II, Technical University of Munich, TUM University Hospital, Munich, Germany",
        "German Cancer Consortium (DKTK), partner site Munich, a partnership between DKFZ and TUM University Hospital, Munich, Germany",
        "TUM School of Medicine and Health, Institute of Molecular Oncology and Functional Genomics, Technical University of Munich, Munich, Germany",
        "TUM School of Medicine and Health, Center for Translational Cancer Research (TranslaTUM), Technical University of Munich, Munich, Germany"
      ],
      "name": "Dieter Saur"
    },
    {
      "affiliations": [
        "Department of Medicine I, Lichtenberg Research Group, Johannes Gutenberg University Hospital Mainz, Mainz, Germany"
      ],
      "name": "Diana Becker"
    },
    {
      "affiliations": [
        "Department of Medicine I, University Medical Center Schleswig Holstein Lübeck Campus, Lübeck, Germany"
      ],
      "name": "Jens U Marquardt"
    },
    {
      "affiliations": [
        "TUM School of Medicine and Health, Institute of Molecular Oncology and Functional Genomics, Technical University of Munich, Munich, Germany",
        "TUM School of Medicine and Health, Center for Translational Cancer Research (TranslaTUM), Technical University of Munich, Munich, Germany"
      ],
      "name": "Rupert Öllinger"
    },
    {
      "affiliations": [
        "TUM School of Medicine and Health, Institute of Molecular Oncology and Functional Genomics, Technical University of Munich, Munich, Germany",
        "TUM School of Medicine and Health, Center for Translational Cancer Research (TranslaTUM), Technical University of Munich, Munich, Germany"
      ],
      "name": "Thomas Engleitner"
    },
    {
      "affiliations": [
        "German Cancer Consortium (DKTK), partner site Munich, a partnership between DKFZ and TUM University Hospital, Munich, Germany",
        "TUM School of Medicine and Health, Institute of Molecular Oncology and Functional Genomics, Technical University of Munich, Munich, Germany",
        "TUM School of Medicine and Health, Center for Translational Cancer Research (TranslaTUM), Technical University of Munich, Munich, Germany"
      ],
      "name": "Roland Rad"
    },
    {
      "affiliations": [
        "TUM School of Medicine and Health, Department for Internal Medicine II, Technical University of Munich, TUM University Hospital, Munich, Germany",
        "German Cancer Consortium (DKTK), partner site Munich, a partnership between DKFZ and TUM University Hospital, Munich, Germany",
        "Bavarian Cancer Research Center (BZKF), Munich, Germany"
      ],
      "name": "Roland M Schmid"
    },
    {
      "affiliations": [
        "TUM School of Medicine and Health, Department for Internal Medicine II, Technical University of Munich, TUM University Hospital, Munich, Germany",
        "German Cancer Consortium (DKTK), partner site Munich, a partnership between DKFZ and TUM University Hospital, Munich, Germany",
        "Bavarian Cancer Research Center (BZKF), Munich, Germany"
      ],
      "name": "Ursula Ehmer"
    }
  ],
  "title": "Activation of RAS/MEK/ERK signalling drives biliary differentiation in primary liver cancer",
  "uid": "6a4fff32-b800-5c92-aa4a-664bafb225f8"
}