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

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.
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Contributor : Angélique Gougelet Connect in order to contact the contributor
Submitted on : Tuesday, January 5, 2021 - 12:07:34 PM
Last modification on : Monday, November 8, 2021 - 10:38:02 AM
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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, BMJ Publishing Group, 2019, 68 (2), pp.322-334. ⟨10.1136/gutjnl-2017-315448⟩. ⟨inserm-02532896⟩



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