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EMBO Mol Med. 2017 Nov;9(11):1589-1604. doi: 10.15252/emmm.201707814.

Mutant CTNNB1 and histological heterogeneity define metabolic subtypes of hepatoblastoma.

Author information

1
Swiss Institute for Experimental Cancer Research, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
2
Bioinformatics Core Facility, SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland.
3
Division of Clinical Pathology, Geneva University Hospitals, Geneva, Switzerland.
4
Department of Pathology, Hôpital Bicêtre, HUPS, Assistance Publique-Hôpitaux de Paris, INSERM U1193, Faculté de Médecine, Université Paris Sud, Paris, France.
5
Swiss Institute of Bioinformatics, Lausanne, Switzerland.
6
Ludwig Center for Cancer Research and Department of Oncology, University of Lausanne, Lausanne, Switzerland.
7
Swiss Institute for Experimental Cancer Research, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland etienne.meylan@epfl.ch.

Abstract

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.

KEYWORDS:

glucose transporter; glycolysis; mutant β‐catenin; pediatric liver cancer

PMID:
28923827
PMCID:
PMC5666308
DOI:
10.15252/emmm.201707814
[Indexed for MEDLINE]
Free PMC Article

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