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    Cell cycle and liver physiopathology

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    Team leader

     

    The liver is an essential organ that performs multiple functions to ensure maintenance of homeostasis. Its main role for detoxification continuously exposes it to several stressors that are poised to induce cellular injuries. The hepatocyte is the most abundant cell of the liver surrounded by others constituting the liver microenvironment. In adults, hepatocytes are quiescent and highly differentiated cells. Distinctively, hepatocytes are polyploid. In eukaryotic organisms, cells usually contain a diploid genome comprised of pairs of homologous chromosomes. Polyploidy refers to gains in entire sets of chromosomes. Throughout life, hepatocytes are constantly exposed to different stressors. Beyond these injuries, hepatocytes retain the unique property to self-renew and to repair the liver ad integrum. In this context, our team is committed to decipher how ploidy, metabolic-genotoxic stress and inflammatory response impact on hepatocytes division integrity during pathological settings.

     

     

    Objectives

    Polyploidization (multiple complete sets of chromosomes) is one of the most dramatic changes that can occur in the genome. The diploid state (2n) is the norm for mammalian cells, but various studies have demonstrated a major role, in specific tissues, of “diploid-polyploid conversion” during physiological processes (e.g. embryogenesis, terminal differentiation) but also during pathological conditions (e.g. genotoxic, metabolic stress, tumorigenesis). Hepatic polyploidy is a characteristic feature of the mammalian liver. Up to 50% of human hepatocytes are polyploid. The roles of hepatic polyploidy represent a major gap in our current understanding of liver biology. We previously demonstrated that polyploidization is initiated during post natal liver growth: hepatocytes accomplish karyokinesis but do not complete cytokinesis. We also showed that the insulin/AKT pathway plays an important role for physiological liver polyploidization. Importantly, throughout life, the liver is constantly exposed to various lesions. Beyond these injuries, hepatocytes retain the unique property to self-renew and to restore the liver ad integrum while preserving its ploidy/DNA integrity; cell-cycle checkpoints are clearly the front line surveillance in this control. Importantly, a long-term consequence of switching to the polyploidization mode during liver tumorigenesis process is still under debate.

    Hepatocellular carcinoma (HCC) is the third most frequent cause of cancer-related deaths worldwide and is a highly heterogeneous disease at the clinical, pathological and molecular levels. More than 80% of HCC develop from a cirrhotic liver after exposure to specific risk factors mainly represented by hepatitis B (HBV) and C (HCV) viral infections, alcohol intake, metabolic disorders and rare genetic diseases. However, the mechanisms leading to hepatocyte cellular transformation are not completely understood. Intensive research in the field of cancer has evidenced the tumour microenvironment (TME) as a fundamental actor during carcinogenesis. The concept of TME is particularly relevant in liver cancer given that >80% of HCC emerge from a disrupted microenvironment.  Recently, using HCC mouse models, we demonstrated that LECT2 (a chemokine-like protein) and invariant Natural Killer T (iNKT) cells are two critical interconnected effectors controlling initiation and progression steps of HCC. Interestingly, our recent data also demonstrated that, immune response driven by LECT2/iNKT affects substantially the balance of ploidy/DNA integrity.

    In this context, our team is committed to understanding mechanistically how ploidy, metabolic, genotoxic stress and inflammatory response impact on cell division integrity and consequently affect tumorigenesis process. Three main projects are developped:

    1- Mechanisms leading to pathological liver polyploidization, functional consequences on tumour outcome. (C. Desdouets)

    2- Maintenance of Hepatocytes Ploidy/DNA Integrity:  Implication of Cell Cycle and Metabolism Checkpoint. (S.Celton-Morizur, C. Desdouets)

    3- Immune Microenvironment (LECT2 and NKTs): Contribution to Hepatocarcinogenesis. (J.P. Couty)

    To reach our goals, the experimental strategy is mainly based on the use of animal model associated with central technologies as hepatocytes primary culture, in vivo liver regeneration, time lapse videomicroscopy, cell sorting, gene expression analyses. Collaboration with clinical team allows us to have access to collection of liver human samples. 


    Main Publications

     

    Gentric G, Maillet V, Paradis V, Couton D, L'Hermitte A, Panasyuk G, Fromenty B, Celton-Morizur S, Desdouets C. Oxidative stress promotes pathologic polyploidization in nonalcoholic fatty liver disease.J Clin Invest. 2015, 125(3):981-92

     
    Gentric G, Desdouets C. Polyploidization in liver tissue. Am J Pathol. 2014,  Feb;184(2):322-31. 

    Merlen G., Gentric G., CELTON-MORIZUR S., Foretz M., Guidotti JE., Fauveau V., Leclerc J., Viollet B., Desdouets C. AMPKα1 controls hepatocyte proliferation independently of energy balance by regulating Cyclin A2 expression. Journal of Hepatology. 2014, Jan; 60(1):152-9.

    Anson M,Crain-Denoyelle AM, Baud V, Chereau F, Gougelet A, Terris B, Yamagoe S, Colnot S, Viguier M, Perret C and Couty JP. Oncogenic beta-catenin triggers an inflammatory response that determines the aggressiveness of hepatocellular carcinoma in mice. J Clin Invest. 2012, 122:586-99

    Espeillac, C., Mitchell, C., Celton-Morizur, S., Chauvin, C., Koka, V., Gillet, C., Albrecht, J. H., Desdouets, C., and Pende, M. S6 kinase 1 is required for rapamycin-sensitive liver proliferation after mouse hepatectomy. J Clin Invest (2011), 121, 2821-2832.

    Celton-Morizur S., Merlen.G., Couton D. and Desdouets C. The insulin/Akt pathway controls a specific cell division program that leads to generation of binucleated tetraploid liver cells in rodents. J Clin Invest. 2009, 119(7): p. 1880-7.


     Funding