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    Oncogenesis of digestive epithelia

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    Team leader

    The major objective of our team is to understand the molecular mechanisms controlling epithelial cell differentiation in the intestine and the liver and to determine how these cellular functions can be subverted during malignant transformation. Using genetically-modified mouse models and human tumor samples, we addressed how developmental pathways, with a focus on the Wnt/β-catenin signalling, control cell fate and cell proliferation and impacted the homeostasis and tumorigenesis of both tissues.  Aberrant activation of the b-catenin signalling is the main initiating event of colorectal cancer and is found in 20-40% of human hepatocellular carcinomas.

    Objectives

    Liver and intestine, two endodermal tissues of the digestive tract, appear highly different in form and function. Intestine has one of the fastest self-renewal rate of all mammalian tissues while liver has a low constitutive regeneration rate, but a strong capacity to regenerate upon acute injury. Our previous research showed that the Wnt/β-catenin pathway play a dual role in intestine by controlling both the renewal of the stem cells located in the crypt and the specification along one intestinal lineage, the Paneth cell. In addition we confirmed the gatekeeper role of the tumor suppressor gene Adenomatous Polyposis Coli (Apc) in colorectal tumorigenesis. In the liver, our previous work identified for the first time activating mutations of CTNNB1 encoding β-catenin gene in human hepatocellular carcinomas and demonstrated that the Wnt/β-catenin signaling has critical role in adult liver physiology being the master developmental pathway involved in the control of  liver metabolic zonation required for its metabolic function. We proposed Apc as the “zonation-keeper” of the liver.

    Two main axes are developed in the team:

              Axe1 : Study of the homeostasis and oncogenesis of the intestinal epithelium (Groupe B. Romagnolo).

              Axe2 : Study of the homeostasis and oncogenesis of the hepatic parenchyma (Groupe S. Colnot, Groupe C. Perret).

     

     

    Main publications

    Canal F, Charawi S, Grimber G, Houbron C, Drouet V, Colnot S, Terris B, Cavard C, Perret C. Generation of Mice with Hepatocyte-Specific Conditional Deletion of Notum. PLoS One. 2016, 11(3):e0150997

    Lévy J, Cacheux W, Bara MA, 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, Romagnolo B. Intestinal inhibition of Atg7 prevents tumour initiation through a microbiome-influenced immune response and suppresses tumour growth. Nat Cell Biol. 2015, 17(8):1062-73.

    Gougelet A, Sartor C, Bachelot L, Godard C, Marchiol C, Renault G, Tores F, Nitschke P, Cavard C, Terris B, Perret C, Colnot S. Antitumour activity of an inhibitor of miR-34a in liver cancer with β-catenin-mutations. Gut. 2016 Jun;65(6):1024-34.

    Dahmani R, Just PA, Delay A, Canal F, Finzi L, Prip-Buus C, Lambert M, Sujobert P, Buchet-Poyau K, Miller E, Cavard C, Marmier S, Terris B, Billaud M, Perret C. A novel LKB1 isoform enhances AMPK metabolic activity and displays oncogenic properties. Oncogene. 2015, 34(18):2337-46

    Gougelet A, Torre C, Veber P, Sartor C, Bachelot L, Denechaud PD, Godard C, Moldes M, Burnol AF, Dubuquoy C, Terris B, Guillonneau F, Ye T, Schwarz M, Braeuning A, Perret C, Colnot S T-cell factor 4 and β-catenin chromatin occupancies pattern zonal liver metabolism in mice. Hepatology. 2014, 59(6):2344-57

     

    Team's news

    • Labeled Team LNCC (Ligue Nationale Contre le Cancer)  since 2005, member of LABEX Who am I ? since 2011, member of SIRIC CARPEM since 2012 and member of the GDR Stem Cell Network since 2016.