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    Targeting the β-catenin activated hepatocarcinomas addiction to fatty acids as a potential therapeutic strategy

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    A study directed by Pascale Bossard, team of Christine Perret

    Hepatocellular carcinoma (HCC) rank as the second leading cause of cancer-related deaths worldwide.

    Pascale Bossard and her colleagues, in Christine Perret team, are looking into the metabolic modifications developed by tumor cells in order to provide the macromolecules and energy sustaining their abnormal growth. In a mouse model developing hepatic tumors with an activation of the oncogene β-catenin (β-catenin induced HCC), the authors show that, contrary to what is observed in most tumors, which are mostly using glucose, the β-catenin induced HCC use fatty acids as their main energy provider. This increased fatty acid catabolism is also observed in human β-catenin induced HCC. They demonstrate that this fatty acid catabolism is mandatory to the transformation process and that inhibiting this metabolic pathway slow down drastically the tumor progression. Inhibiting fatty acid catabolism could be therefore a pertinent therapeutic approach for treating β-catenin HCC. This work has been published in Gut.

    The β-catenin pathway is one of the most frequently dysregulated pathway in human hepatocellular carcinoma (therefore called β-catenin-induced HCC). Despite an improvement in their management, HCC rank as the second leading cause of cancer related death in the world. Pascale Bossard and her colleagues are interested in the metabolic modifications set up by tumor cells to support their higher need in macromolecules and energy for their proliferation. Indeed, in the past years, targeting this metabolic reprograming has emerged as a promising novel therapeutic strategy. Most of the primary or metastatic tumors present a very high rate of glucose consumption (increased glycolysis) compared to normal tissues, this property being widely used to detect these transformed cells using a tracer and medical imaging, the Pet-Scan fluorodeoxiglucose.

    Using a mouse model developing β-catenin induced HCC, Pascale Bossard and her colleagues discovered that contrary to what has been seen in other solid tumors, β-catenin-induced HCC were not at all glycolytic. They show that these HCC use fatty acid oxidation as their main energy provider. This increased fatty oxidation program is also found in a cohort of human β-catenin-induced HCC. Then the authors demonstrated that this metabolic rewiring was mandatory to the oncogenic process and key to the subsequent tumor growth. For that purpose, they have crossed their mouse model with a mouse lacking the transcription factor PPARα, a major actor of fatty acid oxidation in the liver. In absence of PPARα, the number of mice developing β-catenin-induced HCC was strongly diminished and the tumor onset was delayed by several months. Finally, the authors demonstrated that treating the tumor bearing mice with a pharmacological inhibitor of fatty acid oxidation was sufficient to completely slow down the tumor growth rate (figure 2).

    These findings show that the use of fatty acid inhibitors to treat β-catenin-induced HCC appears to be a pertinent therapy since such treatment was able to block their development. Preclinical and clinical trials using different fatty acid oxidation inhibitors has been set up for treating different pathologies but such molecules could be considered for therapeutic approaches to drastically slow down the progression of β-catenin-induced HCC.

     

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    Photo: Lack of lipid accumulation in β-catenin-activated hepatocarcinoma. Lipids (visualised in red) are physiologicaly present in the liver. On the other hand, the increased fatty acid oxidation leads to an absence of lipid storage in β-catenin activated hepatocarcinoma.

    Figure: Treament with a fatty acid oxidation inhibitor drastically slow down tumor growth.