3 years ago

Mutant CTNNB1 and histological heterogeneity define metabolic subtypes of hepatoblastoma

Mutant CTNNB1 and histological heterogeneity define metabolic subtypes of hepatoblastoma
Pierre-Benoit Ancey, Mauro Delorenzi, Catherine Guettier, Olivier Michielin, Vincent Zoete, Stefania Crippa, Etienne Meylan, Anne-Laure Rougemont, Paolo Angelino, Jessica Vazquez
Hepatoblastoma is the most common malignant pediatric liver cancer. Histological evaluation of tumor biopsies is used to distinguish among the different subtypes of hepatoblastoma, with fetal and embryonal representing the two main epithelial components. With frequent CTNNB1 mutations, hepatoblastoma is a Wnt/β-catenin-driven malignancy. Considering that Wnt activation has been associated with tumor metabolic reprogramming, we characterized the metabolic profile of cells from hepatoblastoma and compared it to cells from hepatocellular carcinoma. First, we demonstrated that glucose transporter GLUT3 is a direct TCF4/β-catenin target gene. RNA sequencing enabled to identify molecular and metabolic features specific to hepatoblastoma and revealed that several glycolytic enzymes are overexpressed in embryonal-like compared to fetal-like tumor cells. This led us to implement successfully three biomarkers to distinguish embryonal from fetal components by immunohistochemistry from a large panel of human hepatoblastoma samples. Functional analyses demonstrated that embryonal-like hepatoblastoma cells are highly glycolytic and sensitive to hexokinase-1 silencing. Altogether, our findings reveal a new, metabolic classification of human hepatoblastoma, with potential future implications for patients’ diagnosis and treatment. The fetal and embryonal subtypes of hepatoblastoma (HB), a rare pediatric liver cancer, are shown to represent two distinct metabolic subtypes, potentially offering new avenues for diagnosis or treatment of this malignancy.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.15252/emmm.201707814

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