Institut de recherche biomédicale
     
    Vous êtes ici : Accueil / La Recherche / Développement, Reproduction, Cancer / Equipe C. Desdouets / Liver microenvironment and hepatocarcinogenesis.

    Liver microenvironment and hepatocarcinogenesis.

    •  

     



    Role of the immune microenvironment during liver cancer and diseases


    Principal Investigator

     

    › jean-pierre.couty@inserm.fr

    (33) 1 44 41 24 39

     

    Objective

    Our aim is to understand the functional dialogue between hepatocyte and immune effectors during liver carcinogenesis. Our specific goals are to define the functional roles of immune effectors (LECT2, invariant Natural Killer T cells (iNKT) and other immune partners) during liver tumorigenesis and their impact on hepatocyte cell division, ploïdy/ DNA integrity. Our projects are conducted with the use of  relevant mouse models recapitulating human liver tumorigenesis and vast cohorts of  HCC patients (collaborative studies).

     

    The group

     

     

    Phone number :(33)1 44 41 24 12

    Research interests

    Hepatocellular carcinoma (HCC) is the 3rd leading cause of cancer-related death worldwide. It represents a relevant paradigm of inflammation-associated cancers. Intensive research in the field of cancer evidenced the tumour microenvironment (TME) as a fundamental actor during carcinogenesis (Lévy J et al., 2015, Anson M et al., 2012). The concept of TME is particularly relevant in liver cancer given that more than 80% of HCC emerge from a disrupted microenvironment. Using relevant liver tumor mouse models recapitulating human beta-catenin-induced liver tumorigenesis, we demonstrated that oncogenic β-catenin signaling was able to simultaneously induce in the liver both a pro- and anti-inflammatory program that specified the intensity of the inflammatory response and determined the degree of tumor aggressiveness (Anson M et al., 2012). Two interconnected effectors of the TME were identified, the invariant Natural Killer T cells (iNKT) and LECT2 (Leukocyte cell-derived chemotaxin 2), a hepatocyte secreted factor, as critical cellular and molecular effectors of the TME. Their specific genetic deletion lead to the emergence of highly proliferating and invasive HCC associated with lung metastasis that were never found in the presence of these actors (Anson M et al., 2012). Moreover, we observed that the immune response driven by LECT2/iNKT affects substantially the balance of ploidy/DNA integrity of tumor hepatocytes. These observations prompt us to explore the link between the inflammatory response and ploïdy/DNA integrity, Two main axes are currently developed:

    1-) Phenotypic and functional characterization of immune effectors of the liver focusing on iNKT and LECT2 in terms of function and interactions.

    2-) Impact of the remodeling of the immune microenvironment on cell cycle division, ploïdy/ DNA integrity.



    Main publications

    Lévy J, Cacheux W, Ait Bara M, L’Hermitte A, Lepage P, Fraudeau M, Trentesaux C, Lemarchand J, Durand A, Crain AM, Marchiol C, Renault G, Dumont F, Letourneur F, Delacre M, Schmitt A, Terris B, Perret C, Chamaillard M, Couty JP and Romagnolo B. Intestinal inhibition of Atg7 prevents tumor initiation through a microbiome-influenced immune response and suppresses tumor growth. Nature Cell Biology 2015, 17(8):1062-73.

    Iroz A, Couty JP, Postic C. Hepatokines: unlocking the multi-organ network in metabolic diseases. Diabetologia, 2015;58(8):1699-703.

    Anson M, Crain-Denoyelle AM, Baud V, Chereau F, Gougelet A, Terris B, Yamagoe S, Colnot S, Viguier M, Perret C, Couty JP. Oncogenic β-catenin triggers an inflammatory response that determines the aggressiveness of hepatocellular carcinoma in mice. J Clin Invest. 2012 Feb 1;122(2):586-99.

    Cany J, Barteau B, Tran L, Gauttier V, Archambeaud I, Couty JP, Turlin B, Pitard B, Vassaux G, Ferry N, Conchon S. AFP-specific immunotherapy impairs growth of autochthonous hepatocellular carcinoma in mice. J Hepatol. 2011 Jan;54(1):115-21.

    Couty JP, Lupu-Meiri M, Oron Y, Gershengorn MC. Kaposi's sarcoma-associated herpesvirus-G protein-coupled receptor-expressing endothelial cells exhibit reduced migration and stimulated chemotaxis by chemokine inverse agonists. J Pharmacol Exp Ther. 2009 Jun;329(3):1142-7.

    Hamelet J, Couty JP, Crain AM, Noll C, Postic C, Paul JL, Delabar JM, Viguier M, Janel N. Calpain activation is required for homocysteine-mediated hepatic degradation of inhibitor I kappa B alpha. Mol Genet Metab. 2009 Jun;97(2):114-20.

    Mitchell C, Couton D, Couty JP, Anson M, Crain AM, Bizet V, Rénia L, Pol S, Mallet V, Gilgenkrantz H. Dual role of CCR2 in the constitution and the resolution of liver fibrosis in mice. Am J Pathol. 2009 May;174(5):1766-75.

    Couty JP, Crain AM, Gerbaud S, Labasque M, Marchiol C, Fradelizi D, Boudaly S, Guettier C, Vignuzzi M, van der Werf S, Escriou N, Viguier M. Delivery of mengovirus-derived RNA replicons into tumoural liver enhances the anti-tumour efficacy of a peripheral peptide-based vaccine. Cancer Immunol Immunother. 2008 Aug;57(8):1161-71.

    Decaens T, Godard C, de Reyniès A, Rickman DS, Tronche F, Couty JP, Perret C, Colnot S. Stabilization of beta-catenin affects mouse embryonic liver growth and hepatoblast fate. Hepatology. 2008 Jan;47(1):247-58.

    Couty JP, Rampon C, Leveque M, Laran-Chich MP, Bourdoulous S, Greenwood J, Couraud PO. PECAM-1 engagement counteracts ICAM-1-induced signaling in brain vascular endothelial cells. J Neurochem. 2007 Oct;103(2):793-801.

    Couty JP, Gershengorn MC. G-protein-coupled receptors encoded by human herpesviruses.Trends Pharmacol Sci. 2005 Aug;26(8):405-11.

     

    Financial supports