Genomic Instability, Metabolism, Immunity and Liver Tumorigenesis
Director :
Chantal Desdouets
Deputy Director :
Jean-Pierre Couty
LiverStress is a multidisciplinary team. Our laboratory is involved in basic research in the fields of cell cycle/DNA integrity, immune microenvironment and liver physiopathology. We are particularly interested in metabolic liver diseases and hepatocellular carcinoma.
The team is dedicated to basic and translational research in the field of Liver Physiopathology. The liver is a vital organ responsible for a myriad of functions (e.g. synthesis of proteins, bile production/secretion, metabolism, detoxification). These functions are performed mostly by the hepatocyte, the main liver parenchymal cell. In adults, hepatocytes are quiescent, highly differentiated cells, with the particularity of being polyploid. In eukaryotes, cells usually contain a diploid genome comprised of pairs of homologous chromosomes. Polyploidy refers to gains of 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 project aims to decipher the impact of polyploidy, DNA damage response and immunosurveillance on the integrity of hepatocyte division in pathological situations.
We are particularly interested in overfeeding and/or sedentary lifestyle-associated obesity that promotes Non-Alcoholic Fatty Liver Diseases (NAFLD). NAFLD is a spectrum of chronic liver disease ranging from simple hepatic steatosis (NAFL) to liver cell injury and inflammation known as Non-Alcoholic SteatoHepatitis (NASH). It has already been shown that trends in increasing morbidity and mortality from hepatocarcinomas (HCC) parallel the increasing prevalence of NAFLD.
In that context, our team is committed to understanding mechanistically how polyploidy, DNA damage response and immunosurveillance impact on hepatocytes cell division and transformation leading to HCC emergence and progression.
Scientific Themes
Polyploidy/DNA Damage Response and Liver Metabolic Disorders
Our goal is to determine if DDR and/or Polyploidy act as gatekeepers or drivers of NAFL/NASH progression.
Polyploidy and Consequences on Tumour Outcome
Our aim is to characterize the impact of hepatocytes ploidy modification in vivo on tumor development.
Immune Microenvironment and liver tumorigenesis
Our aim is to unravel the molecular and cellular basis of the crosstalk between hepatocytes and actors of the liver microenvironment (e.g. immune and endothelial cells) under different contexts (metabolic overload and oncogenic).
Main publications
Replication stress triggered by nucleotide pool imbalance drives DNA damage and cGAS-STING pathway activation in NAFLD. Donne R, Saroul-Ainama M, Cordier P, Hammoutene A, Kabore C, Stadler M, Nemazanyy I, Galy-Fauroux I, Herrag M, Riedl T, Chansel-Da Cruz M, Caruso S, Bonnafous S, Öllinger R, Rad R, Unger K, Tran A, Couty JP, Gual P, Paradis V, Celton-Morizur S, Heikenwalder M, Revy P, Desdouets C. Dev Cell, 2022. doi: 10.1016/j.devcel.2022.06.003. link
Structure, Dynamics, and Impact of Replication Stress-Induced Structural Variants in Hepatocellular Carcinoma. Bayard Q, Cordier P, Péneau C, Imbeaud S, Hirsch TZ, Renault V, Nault JC, Blanc JF, Calderaro J, Desdouets C, Zucman-Rossi J, Letouzé E. Cancer Res, 2022. doi: 10.1158/0008-5472. link
Expression of NKG2D ligands is downregulated by β-catenin signalling and associates with HCC aggressiveness. Cadoux M, Caruso S, Pham S, Gougelet A, Pophillat C, Riou R, Loesch R, Colnot S, Nguyen CT, Calderaro J, Celton-Morizur S, Guerra N, Zucman-Rossi J, Desdouets C, Couty JP. J Hepatol, 2021. doi: 10.1016/j.jhep.2021.01.017. link
Polyploidy in Liver Development, Homeostasis and Disease. Donne R, Saroul-Aïnama M, Cordier P, Celton-Morizur S, Desdouets C. Nat Rev Gastroenterol Hepatol, 2020. doi: 10.1038/s41575-020-0284-x. link
Polyploidy spectrum: a new marker in HCC classification. Bou-Nader M, Caruso S, Donne R, Celton-Morizur S, Calderaro J, Gentric G, Cadoux M, L’Hermitte A, Klein C, Guilbert T, Albuquerque M, Couchy G, Paradis V, Couty JP, Zucman-Rossi J, Desdouets C. Gut, 2020. doi: 10.1136/gutjnl-2018-318021. link
Hepatospecific ablation of p38α MAPK governs liver regeneration through modulation of inflammatory response to CCl4-induced acute injury. Fortier M, Cadoux M, Boussetta N, Pham S, Donné R, Couty JP, Desdouets C, Celton-Morizur S. Sci Rep, 2019. doi:10.1038/s41598-019-51175-z. link
Lect2 controls inflammatory monocytes to constrain the growth and progression of hepatocellular carcinoma. 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. Hepatology, 2019. doi: 10.1002/hep.30140. link
LKB1 as a Gatekeeper of Hepatocyte Proliferation and Genomic Integrity during Liver Regeneration. Maillet V, Boussetta N, Leclerc J, Fauveau V, Foretz M, Viollet B, Couty JP, Celton-Morizur S, Perret C, Desdouets C. Cell Rep, 2018. doi: 10.1016/j.celrep.2018.01.086. link
Oxidative stress promotes pathologic polyploidization in nonalcoholic fatty liver disease. Gentric G, Maillet V, Paradis V, Couton D, L’Hermitte A, Panasyuk G, Fromenty B, Celton-Morizur S, Desdouets C. J Clin Invest, 2015. doi: 10.1172/JCI73957. link
All publications
