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    Mechanisms leading to pathological liver polyploidization, functional consequences on tumour outcome.

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    Principal Investigator

    Chantal DESDOUETS, Research director, Ph.D

     chantal.desdouets@inserm.fr
    +33 1 44 41 24 39

     

     

    Polyploidization (multiple complete sets of chromosomes) is one of the most dramatic changes that occur in the genome. The diploid state (2n) is the norm for mammalian cells, but studies have demonstrated a major role, in specific tissues, of “diploid-polyploid conversion” during physiological processes but also in response to numerous environmental and cellular stresses.

    The liver is a physiological polyploid organ (Gentric et al., Am. J of Pathology 2015). Up to 50% of human hepatocytes and 90% of mouse hepatocytes are polyploid; the vast majority being tetraploid with two nuclei (binuclear 2x2n). We previously demonstrated that, during postnatal growth, hepatocytes accomplish adequate karyokinesis but fail to complete cytokinesis (genesis of binuclear cells) (Margal-Ducos et al., J. Cell Science 2007). We also evidenced that during liver development, insulin (through PI3K/Akt pathway) is one of the major actor regulating polyploidization process (Celton-Morizur et al., JCI 2009, Cell Cycle 2010). Importantly, throughout life, the liver is constantly exposed to various stressors. Beyond these injuries, hepatocytes retain the unique property to self-renew and to restore the liver ad integrum while preserving its ploidy/DNA integrity. Nevertheless, how polyploid hepatocytes behave in damaged livers, and their influence in disease progression notably liver cancer are still unanswered questions.

    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 viral infections (HBC, HCV), alcohol intake, and NonAlcoholic Fatty Liver Disease (NAFLD), the hepatic manifestation of metabolic syndrome. The dissection of the early events of liver carcinogenesis is a major issue in order to understand the underlying pathogenesis of the disease. Which role can be assigned to polyploidy in this oncogenic process? It is tempting to speculate that pre-existing polyploidy could serve as “hit en route” to liver cancer. We recently uncover that pathological polyploidization takes place during NAFLD. Alarmingly, NAFLD progresses pejoratively to NonAlcoholic SteatoHepatitis (NASH) and evolve in some cases to hepatocellular carcinoma. The prevalence of NAFLD is currently estimated to range 5 to 20% in the general population. Interestingly, using murine NAFLD models and cohort of patients, we recently demonstrated the conversion of a physiological polyploidy (binuclear 2x2n, DNA integrity) towards a pathological polyploidy (mononuclear 4n, ≥8n, DNA instability). Of note, this polyploid contingent is generated under a "DNA damage signal" (ATR/p53/p21) that precludes the activation of mitotic kinase (endoreplication cycle). Importantly, oxidative stress was evidenced as a key player. Indeed, antioxidant treatment (NAC) was sufficient to: (1) dampen ROS level in damaged liver, (2) inhibit ATR activation, (3) restore a normal polyploid status. Collectively, these new findings demonstrate for the first time within damaged liver, the genesis of pathological polyploid hepatocytes exhibiting a strong potential of genomic instability (Gentric and Desdouets, Oncotarget 2015; Gentric et al., JCI 2015) 

     

    Objective

    The main goal of our project is now to determine how pathological polyploid cells behave in damaged liver and their relevance during disease progression. Our project is divided into different axes: (1) Determination of the mechanisms linking oxidative/DNA replication stress to pathological polyploidy. (2) Define the outcome of polyploid fraction in terms of proliferation, DNA integrity and immune recognition (3) Determination of polyploid profiles related to genomic alterations as a potent prognostic marker for HCC. To reach our goals, the experimental strategy is mainly based on the use of animal models associated with central technologies as hepatocytes primary culture, specific ploidy cell sorting, omics analyses and dedicated quantitative ploidy imaging system. Translational research is performed in collaboration with clinical teams.

     

    The group

    Myriam BOU-NADER - Post-Doctoral Fellow (Inserm)
    Vanessa MAILLET – PhD Student (Université Paris Descartes)
    Romain DONNE  - Master 2 Student (Université Pierre et Marie Curie)
    Nadia BOUSETTA – ITA (Inserm)

    Main publications and patents

    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. Liver polyploidy: Dr Jekyll or Mr Hide? Oncotarget (2015), 6(11):8430-1.

    Gentric, G. and Desdouets, C. Polyploidization in Liver Tissue.  Am J Pathol (2014), 184 (2): 322-31.

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

    Gasnereau, I., Boissan, M., Margall-Ducos, G., Couchy, G., Wendum, D., Bourgain-Guglielmetti, F., Desdouets, C., Lacombe, M. L., Zucman-Rossi, J., and Sobczak-Thepot, J. KIF20A mRNA and its product MKlp2 are increased during hepatocyte proliferation and hepatocarcinogenesis. Am J Pathol, 2012, 180, 131-140.

    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. Polyploidy and liver proliferation: Central role of insulin signaling. Cell Cycle, 2010, 9 (3):460-6.

    Pulecio, J., Petrovic, J., Prete, F., Chiaruttini, G., Lennon-Dumenil, A. M., Desdouets, C., Gasman, S., Burrone, O. R., and Benvenuti, F. Cdc42-mediated MTOC polarization in dendritic cells controls targeted delivery of cytokines at the immune synapse. J Exp Med, 2010, 207, 2719-2732.

    Celton-Morizur S, Merlen G, Couton D, Margall-Ducos G 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.

    Margall-Ducos, G., Celton-Morizur, S., Couton, C., Bregerie, O. & Desdouets C. Liver tetraploidization is controlled by a new process of incomplete cytokinesis. J Cell Science.2007, 120(20): 3633-39.

     

    Financial supports