β-catenin-activated hepatocellular carcinomas are addicted to fatty acids - Archive ouverte HAL Access content directly
Journal Articles Gut Year : 2019

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

(1) , (1) , (1) , (1) , (1) , (1) , (1) , (2, 1) , (1) , (1) , (1) , (1)
1
2
Nadia Senni
  • Function : Author
Mathilde Savall
  • Function : Author
Marie-Clotilde Alves-Guerra
Chiara Sartor
  • Function : Author
Angélique Gougelet
  • Function : Author
  • PersonId : 966825
Hélène Gilgenkrantz
  • Function : Author
  • PersonId : 945880
Christine Perret
Sabine Colnot
  • Function : Author
Pascale Bossard

Abstract

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.
Embargoed file
Embargoed file
Ne sera jamais visible

Dates and versions

inserm-02532896 , version 1 (05-01-2021)

Identifiers

Cite

Nadia Senni, Mathilde Savall, David Cabrerizo Granados, Marie-Clotilde Alves-Guerra, Chiara Sartor, et al.. β-catenin-activated hepatocellular carcinomas are addicted to fatty acids. Gut, 2019, 68 (2), pp.322-334. ⟨10.1136/gutjnl-2017-315448⟩. ⟨inserm-02532896⟩
45 View
2 Download

Altmetric

Share

Gmail Facebook Twitter LinkedIn More