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

Nadia Senni1,2,3,4, Mathilde Savall1,2,3,4, David Cabrerizo Granados1,2,3,4

  • 1INSERM, U1016, Institut Cochin, Paris, France.

Gut
|April 14, 2018
PubMed
Abstract

Insights

Hepatocellular carcinoma (HCC) driven by CTNNB1 mutations relies on fatty acid oxidation (FAO) for growth. Inhibiting FAO effectively blocks tumor development, offering a new therapeutic strategy for CTNNB1-mutated HCC.

Area of Science:

  • Hepatocellular carcinoma (HCC) research
  • Cancer metabolism
  • Molecular oncology

Background:

  • CTNNB1-mutated HCC is a significant subtype of liver cancer with limited targeted therapy options.
  • The metabolic reprogramming induced by oncogenic beta-catenin activation in HCC remains poorly understood.
  • Investigating these metabolic alterations may reveal novel therapeutic targets.

Purpose of the Study:

  • To decipher the metabolic reprogramming induced by oncogenic beta-catenin activation in the liver.
  • To assess the role of fatty acid oxidation (FAO) in CTNNB1-mutated HCC development.
  • To evaluate FAO inhibition as a potential therapeutic strategy for CTNNB1-mutated HCC.

Main Methods:

  • Utilized mouse models with hepatocyte-specific beta-catenin activation to study metabolic fluxes.
  • Assessed the role of Peroxisome proliferator-activated receptor alpha (PPARα) in knockout mice.
  • Analyzed the impact of fatty acid oxidation (FAO) inhibition using etomoxir.
  • Explored FAO pathway gene expression in human HCC datasets.

Main Results:

  • Beta-catenin-activated HCC exhibited significant fatty acid oxidation (FAO) rather than glycolysis.
  • PPARα was identified as a direct beta-catenin target gene crucial for FAO metabolic reprogramming.
  • Deletion of PPARα inhibited the initiation and progression of beta-catenin-dependent HCC.
  • FAO pathway activation was observed in human CTNNB1-mutated HCC, regulated by PPARα.

Conclusions:

  • Fatty acid oxidation (FAO) is the primary driver of beta-catenin-induced HCC.
  • Inhibition of FAO, through genetic or pharmacological means, effectively blocks HCC development.
  • Targeting FAO presents a promising therapeutic approach for CTNNB1-mutated hepatocellular carcinoma.
Keywords:
hepatocellular carcinomalipid oxidationliver metabolism

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