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@ARTICLE{Rsner:301297,
      author       = {T. Rösner and C. Rupp and C. Lechler and U. Bauer and S.
                      S. Manmadhan and S. Bernatik and F. Delugré and F. Ihli and
                      T. Derowski and S. Jörs and B. Kohnke-Ertel and H.
                      Einwächter and N. Pfarr$^*$ and K. Steiger$^*$ and C.
                      Mogler$^*$ and M. Reichert$^*$ and D. K. M. Saur$^*$ and D.
                      Becker and J. U. Marquardt and R. Öllinger and T.
                      Engleitner and R. Rad$^*$ and R. M. Schmid$^*$ and U.
                      Ehmer$^*$},
      title        = {{A}ctivation of {RAS}/{MEK}/{ERK} signalling drives biliary
                      differentiation in primary liver cancer.},
      journal      = {Gut},
      volume       = {74},
      number       = {10},
      issn         = {0017-5749},
      address      = {London},
      publisher    = {BMJ Publishing Group},
      reportid     = {DKFZ-2025-00980},
      pages        = {1653-1666},
      year         = {2025},
      note         = {2025 Sep 8;74(10):1653-1666},
      abstract     = {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.The objective of this study was to investigate
                      RAS-dependent signalling pathways in CCA and their role in
                      tumour development and differentiation.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.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.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.},
      keywords     = {CANCER GENETICS (Other) / CHOLANGIOCARCINOMA (Other) /
                      HEPATOBILIARY CANCER (Other)},
      cin          = {MU01},
      ddc          = {610},
      cid          = {I:(DE-He78)MU01-20160331},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40355258},
      doi          = {DOI:10.1136/gutjnl-2024-333238},
      url          = {https://inrepo02.dkfz.de/record/301297},
}