β-catenin-activated hepatocellular carcinomas are addicted to fatty acids
N Senni, M Savall, DC Granados, MC Alves-Guerra… - Gut, 2019 - gut.bmj.com
N Senni, M Savall, DC Granados, MC Alves-Guerra, C Sartor, I Lagoutte, A Gougelet…
Gut, 2019•gut.bmj.comObjectives 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 …
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 …
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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