β-catenin-activated hepatocellular carcinomas are addicted to fatty acids.

Abstract

<i>CTNNB1</i>-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 <i>CTNNB1</i>-mutated HCC. 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 <i>Pparα</i> 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. β-catenin-activated HCC were not glycolytic but intensively oxidised fatty acids. We found that <i>Pparα</i> is a β-catenin target involved in FAO metabolic reprograming. Deletion of <i>Pparα</i> was sufficient to block the initiation and progression of β-catenin-dependent HCC development. FAO was also enriched in human <i>CTNNB1</i>-mutated HCC, under the control of the transcription factor PPARα. 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 <i>CTNNB1</i>-mutated HCC.