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Proliferation, Stress and Liver Physiopathology

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. Theses cells are also characterized by variation in DNA content: polyploidy, an increase in the number of chromosome sets per cell. Remarkably, hepatocytes retain the unique property in the whole body to exit quiescent state, self-renew and restore liver parenchyma ad integrum while preserving its DNA integrity. Due to its central position into the body, the liver exposes constitutively hepatocytes to various stressors, such as oxidative stress, metabolic overload and inflammation sensitizing these them to malignant transformation. Alarmingly, hepatocellular carcinoma (HCC) ranks at the second leading cause of cancer related death worldwide. More than 90% of HCCs in Western countries develop on a cirrhotic background as a result of chronic hepatitis B or C infection, high alcohol intake, or nonalcoholic fatty liver disease (NAFLD). NAFLD is a spectrum of chronic liver disease ranging from simple hepatic steatosis to liver cell injury and inflammation known as Non-Alcoholic SteatoHepatitis (NASH). Nowadays, it is already demonstrated that HCC’s escalating morbidity and mortality trends parallel to the rising prevalence of NAFLD due to the growing epidemic of obesity and diabetes.
In that context, our team is committed to understanding mechanistically how polyploidy, DNA damage response and immunosurveillance impact on hepatocytes division and consequently to HCC development. Three main projects are developed:

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: Contribution to Hepatocarcinogenesis (J.P. Couty).

 

To reach our goals, our experimental strategy is mainly based on the development of relevant mouse models mimicking different stages of human hepatocarcinogenesis. Leading-edge technologies are mastered as hepatocytes primary cultures, in vivo liver regeneration, ploidy/immuno-digital imaging systems, flow cytometry/cell sorting. Clinical and translational researches are based on strong collaborations with different hepato/anatomopathology departments.

 

Team Leader : Chantal DESDOUETS (DR; Inserm)

 

Team Members :

Researchers: Jean Pierre COUTY (MCU; Paris Diderot), Séverine CELTON-MORIZUR (CR; Inserm),

Technical Staff: Jocelyne LECLERC (IR; Inserm)

Young Researchers: Mathilde CADOUX (PhD Student), Sandrine PHAM (PhD Student), Romain DONNE (PhD Student), Maeva SAROUL (PhD Student).

Students: Pierre CORDIER (Master Student), Christelle KABORE (Master Student), Céline POPHILLAT (Master Student).

 

  


Contact : Chantal Desdouets

 


PUBLICATIONS

  • L'Hermitte A, Pham S, Cadoux M, Couchy G, Caruso S, Anson M, Crain-Denoyelle AM, Celton-Morizur S, Yamagoe S, Zucman-Rossi J, DESDOUETS C, Couty JP. Lect2 controls inflammatory monocytes to constrain the growth and progression of hepatocellular carcinoma. Hepatology. 2018. doi: 10.1002/hep.30140.
  • Maillet V, Boussetta N, Leclerc J, Fauveau V, Foretz M, Viollet B, Couty JP, Celton-Morizur S, Perret C, Desdouets C. LKB1 as a gatekeeper of hepatocyte proliferation and genomic integrity during liver regeneration. Cell Report 2018, 22: 1994-2005.
  • 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: 981-92.
  • 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.
  • 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: 1880-1887.

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