Activation of RAS/MEK/ERK signalling drives biliary differentiation in primary liver cancer
Menée à l'aide de modèles murins avec activation oncogène de Kras et délétion spécifique des suppresseurs de tumeur Rb et p53 dans les hépatocytes, cette étude met en évidence un mécanisme par lequel l'activation de la voie de signalisation "RAS/MEK/ERK" favorise le développement d'un cholangiocarcinome intrahépatique à partir des hépatocytes
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.
Gut , résumé, 2025