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Activation of RAS/MEK/ERK signalling drives biliary differentiation in primary liver cancer

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 inve...

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Autores principales: Rösner, Thomas (Autor) , Rupp, Carina (Autor) , Lechler, Christian (Autor) , Bauer, Ulrike (Autor) , Manmadhan, Saumya Sukumary (Autor) , Bernatik, Sophia (Autor) , Delugré, Fabian (Autor) , Ihli, Franziska (Autor) , Derowski, Tanja (Autor) , Jörs, Simone (Autor) , Kohnke-Ertel, Birgit (Autor) , Einwächter, Henrik (Autor) , Pfarr, Nicole (Autor) , Steiger, Katja (Autor) , Mogler, Carolin (Autor) , Reichert, Maximilian (Autor) , Saur, Dieter (Autor) , Becker, Diana (Autor) , Marquardt, Jens U. (Autor) , Öllinger, Rupert (Autor) , Engleitner, Thomas (Autor) , Rad, Roland (Autor) , Schmid, Roland M. (Autor) , Ehmer, Ursula (Autor)
Formato: Article (Journal)
Lenguaje:inglés
Publicado: 12 May 2025
In: Gut
Year: 2025, Volumen: 74, Número: 10, Pages: 1653-1666
ISSN:1468-3288
DOI:10.1136/gutjnl-2024-333238
Acceso en línea:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1136/gutjnl-2024-333238
Verlag, lizenzpflichtig, Volltext: https://gut.bmj.com/content/74/10/1653
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Notas de Autor:Thomas Rösner, Carina Rupp, Christian Lechler, Ulrike Bauer, Saumya Sukumary Manmadhan, Sophia Bernatik, Fabian Delugré, Franziska Ihli, Tanja Derowski, Simone Jörs, Birgit Kohnke-Ertel, Henrik Einwächter, Nicole Pfarr, Katja Steiger, Carolin Mogler, Maximilian Reichert, Dieter Saur, Diana Becker, Jens U. Marquardt, Rupert Öllinger, Thomas Engleitner, Roland Rad, Roland M. Schmid, Ursula Ehmer
Descripción
Sumario: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.
Notas:Gesehen am 21.05.2026
Descripción Física:Online Resource
ISSN:1468-3288
DOI:10.1136/gutjnl-2024-333238

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