%0 Journal Article
%A Rösner, Thomas
%A Rupp, Carina
%A Lechler, Christian
%A Bauer, Ulrike
%A Manmadhan, Saumya Sukumary
%A Bernatik, Sophia
%A Delugré, Fabian
%A Ihli, Franziska
%A Derowski, Tanja
%A Jörs, Simone
%A Kohnke-Ertel, Birgit
%A Einwächter, Henrik
%A Pfarr, Nicole
%A Steiger, Katja
%A Mogler, Carolin
%A Reichert, Maximilian
%A Saur, Dieter Karl Maximilian
%A Becker, Diana
%A Marquardt, Jens U
%A Öllinger, Rupert
%A Engleitner, Thomas
%A Rad, Roland
%A Schmid, Roland M
%A Ehmer, Ursula
%T Activation of RAS/MEK/ERK signalling drives biliary differentiation in primary liver cancer.
%J Gut
%V 74
%N 10
%@ 0017-5749
%C London
%I BMJ Publishing Group
%M DKFZ-2025-00980
%P 1653-1666
%D 2025
%Z 2025 Sep 8;74(10):1653-1666
%X 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.
%K CANCER GENETICS (Other)
%K CHOLANGIOCARCINOMA (Other)
%K HEPATOBILIARY CANCER (Other)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:40355258
%R DOI:10.1136/gutjnl-2024-333238
%U https://inrepo02.dkfz.de/record/301297