Gut · 2025
Activation of RAS/MEK/ERK signalling drives biliary differentiation in primary liver cancer.
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Rösner Thomas, Rupp Carina, Lechler Christian, Bauer Ulrike, Manmadhan Saumya Sukumary, Bernatik Sophia, Delugré Fabian, Ihli Franziska, Derowski Tanja, Jörs Simone, Kohnke-Ertel Birgit, Einwächter Henrik, Pfarr Nicole, Steiger Katja, Mogler Carolin, Reichert Maximilian, Saur Dieter, Becker Diana, Marquardt Jens U, Öllinger Rupert, Engleitner Thomas, Rad Roland, Schmid Roland M, Ehmer Ursula
Аннотация
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.
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.
Предметные рубрики MeSH
Carcinoma, HepatocellularLiver NeoplasmsMutationMAP Kinase Signaling SystemLiverMice, TransgenicProto-Oncogene Proteins p21(ras)Gene Expression Regulation, NeoplasticTumor Suppressor Protein p53Retinoblastoma ProteinCholangiocarcinomaCell TransdifferentiationHepatocytesWnt Signaling PathwayHumansAnimalsMiceMaleCell Line, TumorBile Duct NeoplasmsBile Ducts, IntrahepaticRetinoblastoma Binding Proteins