Biomedical research institute
    You are here: Home / PhD program / Thesis defense / Study of the response to oxydative stress in β-catenin activated hepatocellular carcinomas

    Study of the response to oxydative stress in β-catenin activated hepatocellular carcinomas


    Mathilde Savall


    Thursday 9th of April 2020 2 pm

    Rosalind Franklin room

    Institut Cochin, 22 rue Méchain, Paris 75014


    Hepatocellular carcinoma (HCC) is the 2nd leading cause of cancer related death worldwide. For many years, our team has been interested in β-catenin activated HCC which represent 30 to 40% of all HCCs. With murine models mimicking carcinogenesis, we were able to show that these tumors present an increase in fatty acid oxidation. We also showed that this β-oxidation is essential for β-catenin activated tumorigenesis and tumor progression and that they present an increased activity of the mitochondrial respiration chain.

    β-catenin activated cells also have an increased expression of P450 cytochromes which, with the increase of mitochondrial respiration chain, are known to generate reactive oxygen species (ROS). ROS accumulation can create an oxidative stress which is deleterious for the cell if not taken in charge by an anti-oxidantdefense (AOD). Cancer cells are known to have a high level of ROS that requires the establishment of an AOD in order to survive and proliferate. By changing the AOD, it is possible to modify the redox balance and hence reach a toxic threshold leading to cell death without compromising normal cells.

    Theaims of my PhD were to 1) characterize the redox status of these tumors, 2) to identify the protection mechanisms again oxidative stress and 3) to see if it could be used as a therapeutic approach. 

    My results show that pre-neoplasic β-catenin activated cells generate a bigger amount of ROS but that theyare better protected against oxidative stress thanks to the activation of the Nrf2 pathway. This should explain the tumoral growth seen in this deleterious context. We also showed that the inhibition of the Nrf2 program with a pharmacological inhibitor (Halofuginone) is deleterious for these cells. Moreover, after having shown that β-catenin activated tumors are also protected thanks to the Nrf2 pathway, we also demonstrate that Halofuginone treatments lead to a decrease in tumor growth rate. Interestingly, thanks to the analyses of the TCGA data, we were able to show that an Nrf2 signature is associated with CTNNB1-mutated HCCs and that this program worsen the prognosis of CTNNB1 mutated patients. Hence, the inhibition of the Nrf2 program could be an anti-cancer strategy to target β-catenin activated HCCs.  My resultats also showed that the Nrf2 program participate in the metabolic phenotype of pre-neoplasic β-catenin activated hepatocytes. Indeed, the oncogenic activation of the β-catenin lead the an increased β-oxydation in which Nrf2 rewire acetyl coA towards the Krebs cycle at the expense of ketogenesis. Moreover, our studie showed that β-catenin activated cells are sensible to Acetaminophen (APAP) because of the increased expression of cytochromes P450. APAP treatments lead to the death of β-catenin activated tumoral cells and to the decrease of the tumoral growth. In conclusion, this study shows to possible anti-cancer strategies by using the redox balance.