Institut de recherche biomédicale
     
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    Maintien de la ploïdie hépatocytaire et de l’intégrité génomique : Implication des points de contrôle métabolique et du cycle cellulaire

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    Principal Investigators:

     

    Objectives

    This part of the project aims to define what are the different checkpoints (metabolic, cell cycle …) regulating hepatocyte proliferation in the liver to ensure maintenance of physiological ploidy and genomic integrity. Furthermore, we are also focusing on the impact and the outcome of an abnormal proliferative/ploidy status during pathological context, notably during HCC development. Our projects are conducted with the use of relevant mouse models involving alteration of these pathways (Liver specific KO) and vast cohorts of HCC patients (collaborative studies).

     

    Research interest

    Cellular polyploidization is now well-known to be correlated to chromosomal instability appearance and carcinogenesis process development. Indeed, in some tumor types, there is a direct evidence for the development of aneuploidy from a transient tetraploid (4N) state. Given the apparent dangers, it is logical that cells have evolved mechanisms to prevent the proliferation or survival of tetraploid cells. Indeed, newly generated tetraploid cells undergo a p38/p53 dependent cell cycle arrest in G1 phase that conduct either to apoptotic death or senescence state. However, tetraploid cells can bypass this checkpoint and progress into mitosis. In this condition, the Spindle Assembly Checkpoint (SAC) is activated and exerts an additional level of control to maintain DNA integrity (genesis of polyploid contingent instead of aneuploid). Altered expression of SAC components has been documented in numerous human cancers. In that context, proliferating cells are exposed in anaphase to chromosome misegregation leading to aneuploidy status.

    Normal liver is mainly constituted of tetraploid hepatocytes (40% in humans). Due to the constant exposure of hepatocytes to DNA damage (genotoxic and metabolic stress), the liver has to develop specific checkpoints to preserve genomic integrity. Recently, we and others have pointed out that p38 MAPK and p53 act as negative regulators of the proliferative state of polyploid hepatocytes during liver development. Moreover, we have shown in collaboration with C.Perret’s group that the master kinase LKB1, which regulates both metabolic status and cell polarity, was also controlling hepatocyte proliferation process and DNA integrity. During in vivo regeneration experiments, we found that its absence induces mitotic defects leading to SAC activation. Altogether, these results reveal that hepatocyte proliferation is intricately regulated at several levels in order to maintain physiological polyploidy and consequently ensure genome integrity in hepatic tissue.

    In that context, the project aims to define whether the bypass of these checkpoints could (1) alterate hepatocytes proliferation and liver homeostasis, (2) facilitate the emergence of cellular aneuploidy and (3) then be associated to a CIN signature inside hepatocyte genome. Moreover, we will (4) determine if emergence of a specific ploidy profile could be related to a peculiar molecular signature during human hepatocarcinoma development and could be then used as a biomarker (detection / early diagnosis).

     

    Main publications

    Liver polyploidy: Dr Jekyll or Mr Hide? Gentric G., Desdouets C. Oncotarget, 2015, Apr 20;6(11):8430-1.

    Oxidative Stress Promotes Pathological Liver Polyploidization in NAFLD. Gentric G., Maillet V., Paradis V., Couton D., L’Hermitte A., Panasyuk G., Fromenty B., Celton-Morizur S.* and Desdouets C.* Journal of Clinical Investigation, 2015, Mar 2, 125(3):981-92. *Co-last authors.

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

    Polyploidization without mitosis improves in vivo liver transduction with lentiviral vectors. Pichard V., Couton D., Desdouets C., Ferry N. Hum Gene Ther, 2013 Feb;24(2):143-51.

    Regulation of the hepatocyte cell cycle: signaling pathways and protein kinases. Loyer P., Corlu A., Desdouets C. Int J Hepatol, 2012;2012:592354.

    Hepatocytes polyploidization and cell cycle control in liver physiopathology. Gentric G, Desdouets C, Celton-Morizur S. Int J Hepatol. 2012;2012:282430.

    Polyploidy and liver proliferation. Gentric G., Celton-Morizur S., Desdouets C. Clinical Research in Hepatology and Gastroenterology, 2012 Feb; 36(1):29-34.

    KIF20A mRNA and its product MKlp2 are increased during hepatocyte proliferation and hepatocarcinogenesis. Gasnereau I., Boissan M., Margall-Ducos G., Couchy G., Wendum D., Bourgain-Guglielmetti F., Desdouets C., Lacombe ML., Zucman-Rossi J., Sobczak-Thépot J. Am J Pathol, 2012 Jan;180(1):131-40.

    S6 kinase 1 activity accounts for rapamycin-sensitive liver proliferation after mouse hepatectomy. Espeillac C.*, Mitchell C.*, Celton-Morizur S.*, Chauvin C., Albrecht J.H., Desdouets C. et Pende M. Journal of Clinical Investigation, 2011, Jul;121(7):2821-32. *Co-first authors.

    Polyploidy and liver proliferation: Central role of insulin signalling. Celton-Morizur, S., Merlen.G., Couton D. and Desdouets C. Cell cycle, 2010, Feb 1;9(3):460-6.

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

     

    The group



    Financial support