Objectives CTNNB1-mutated hepatocellular carcinomas (HCCs) constitute a major part of human HCC and are largely inaccessible to target therapy. Yet, little is known about the metabolic reprogramming induced by β-catenin oncogenic activation in the liver. We aimed to decipher such reprogramming and assess whether it may represent a new avenue for targeted therapy of CTNNB1-mutated HCC.
Design We used mice with hepatocyte-specific oncogenic activation of β-catenin to evaluate metabolic reprogramming using metabolic fluxes on tumourous explants and primary hepatocytes. We assess the role of Pparα in knock-out mice and analysed the consequences of fatty acid oxidation (FAO) using etomoxir. We explored the expression of the FAO pathway in an annotated human HCC dataset.
Results β-catenin-activated HCC were not glycolytic but intensively oxidised fatty acids. We found that Pparα is a β-catenin target involved in FAO metabolic reprograming. Deletion of Pparα was sufficient to block the initiation and progression of β-catenin-dependent HCC development. FAO was also enriched in human CTNNB1-mutated HCC, under the control of the transcription factor PPARα.
Conclusions FAO induced by β-catenin oncogenic activation in the liver is the driving force of the β-catenin-induced HCC. Inhibiting FAO by genetic and pharmacological approaches blocks HCC development, showing that inhibition of FAO is a suitable therapeutic approach for CTNNB1-mutated HCC.
- liver metabolism
- hepatocellular carcinoma
- lipid oxidation
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CP and SC contributed equally.
Contributors PB: conceived and supervised the study, analysed the data, carried out the experiments, wrote the manuscript and funding. NS: designed and carried out experiments and analysed the data. MS, DCG and CS: performed experiments. AG: technical advises and reading of the manuscript. IL: acquisition of ultrasound data. HG: axin1 animal model and critical reading of the manuscript. BT: provided the human samples. CP: funding, heatmap generation and analysis, critical revision of the data and critical reading of the manuscript. SC: funding, GSEA analysis and critical reading of the manuscript.
Funding NS is a recipient of Ligue Nationale Contre le Cancer (LNCC) and ARC foundation scholarships. MS is a recipient of the French Ministry of Research scholarship. This study was supported by grants from the ANR (Agence Nationale de la Recherche), the AFEF (Association Française d’Hépatologie) and the LNCC.
Competing interests None declared.
Patient consent Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
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