Equipe d’Accueil : LIVER-STRESS

Intitulé de l’Unité : Centre de Recherche des Cordeliers, INSERM U1138

Nom du Responsable de l’Unité : Jessica Zucman-Rossi

Nom du Responsable de l’Équipe : Chantal Desdouets

Adresse : 15 rue de l’Ecole de Médecine 75006 PARIS

Responsable de l’encadrement : Séverine Celton-Morizur

Tél : 0144272477 E-mail:  severine.morizur@inserm.fr

Résumé du projet :

Hepatocellular carcinoma (HCC) is a significant global health concern, ranking among the five most common adult cancers with rising incidence and mortality. The prognosis remains poor, with five-year survival rates below 20%, largely due to late diagnosis, aggressive tumor behavior, and resistance to chemotherapy. Despite extensive efforts to develop effective systemic treatments, a new and alarming risk factor has emerged: metabolic dysfunction-associated steatotic liver disease (MASLD), driven by chronic overeating and sedentary lifestyles (commonly referred to as fatty liver disease or soda disease).

MASLD, characterized by excessive fat accumulation in the liver (steatosis), affects about 25% of the European population. This condition can progress to a more severe inflammatory form known as metabolic dysfunction-associated steatohepatitis (MASH), which is a precursor to HCC. To improve diagnosis and treatment, it is crucial to understand the underlying mechanisms driving the progression from MASLD to HCC.

Our laboratory has shown that the livers of MASH patients exhibit significant DNA damage. Using preclinical models of MASLD, we discovered that steatotic hepatocytes show signs of replication stress, including slowed DNA replication and an ATR-mediated DNA damage response. These stressed cells also displayed DNA damage, cytoplasmic DNA leakage, and activation of the cGAS-STING pathway, which leads to the production of type I interferons. Our findings further suggest that lipid overload alone is sufficient to trigger replication stress, DNA damage and cGAS-STING activation, proposing a potential mechanism for disease progression.

The M2 project will investigate the intricate role of cGAS-STING signaling in MASLD-related liver cancer. Specifically, the research aims to:

  • Determine if cGAS-STING signaling acts as a gatekeeper or a driver of MASLD/HCC.
  • Explore the pathway’s role in metabolic reprogramming, beyond its known inflammatory function.

The experimental approach will primarily utilize relevant mouse models that mimic both MASLD/MASH conditions with mutations in STING and cGAS, allowing for a detailed investigation of their individual and combined effects. The M2 student undertaking this project will benefit from a highly collaborative research environment and gain proficiency in a range of cutting-edge technological approaches (Digital pathology, Multispectral imaging, RNA-Seq analyses, Flow cytometry…).

 

Dernières Publications en lien avec le projet :

  • Cho MG, Lee R, Johnson J, Gupta GP. Molecular mechanisms regulating cGAS/STING activation in health and disease. J Clin Invest. 2026 Jul 1;136(13):e204548. doi: 10.1172/JCI204548. PMID: 42383355; PMCID: PMC13318112.
  • 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. Replication stress triggered by nucleotide pool imbalance drives DNA damage and cGAS-STING pathway activation in NAFLD. Dev Cell. 2022 Jul 25;57(14):1728-1741.e6. doi: 10.1016/j.devcel.2022.06.003. Epub 2022 Jun 28. PMID: 35768000.
  • Anstee QM, Reeves HL, Kotsiliti E, Govaere O, Heikenwalder M. From NASH to HCC: current concepts and future challenges. Nat Rev Gastroenterol Hepatol. 2019 Jul;16(7):411-428. doi: 10.1038/s41575-019-0145-7. PMID: 31028350.

 

Ce projet s’inscrit-il dans la perspective d’une thèse :   oui  x           non o

si oui type de financement prévu : contrat doctoral