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    Identity and oncogenesis of liver parenchyma

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    Principal investigator: Christine Perret

     christine.perret@inserm.fr
    + 33 (0)1 44 41 25 64

     

    Objective

    The liver is the central metabolic organ in vertebrate body. Its functions range from lipid synthesis over glycogen storage and production of serum proteins. Most of these functions are performed by hepatocytes, one of the epithelial cell types in the liver. The other epithelial cell type, the cholangiocyte or biliary epithelial cell, forms ducts that collect and modify bile secreted by hepatocytes. Our objectives aim at deciphering the molecular events that are involved in the homeostasis and oncogenesis of the liver with a focus on the Wnt/β-catenin signaling.

     

    Research interests.

    1. Role of Notum and Lkb1 during the liver physiopathology (CP)
      Our past results led us to study the role of two actors of the liver physiopathology, Notum and Lkb1. NOTUM is a β-catenin target gene that we identified as one of the most up-regulated in human HCC mutated for CTNNB1. Notum was described to be involved in the Wg morphogen signal in drosophila. We decided to study its role in the liver by creating a mouse model of conditional inactivation of Notum. The specific morphological and metabolic profile of human HCC with CTNNB1 mutations led us to study the role of Lkb1 in these tumors
    2. Sudy of the metabolic reprogramming during liver tumorigenesis induced by an aberrant activation of the β-catenin signaling (PB, SC).
      Human CTNNB1 HCC revealed a specific metabolic profile that we studied using the ApcKO mouse model that we established in the team. This study led us to show that, in contrast to most of tumors that used glucose as energetic fuel (Warburg effect), HCC with aberrant β-catenin signaling used lipids. We study the involved metabolic pathways to identify therapeutic targets.
    3.  Role of Axin1 in liver physiopathology (HG, CP).
      AXIN1 is described as a negative regulator of the β-catenin signaling, it belongs, as APC, to the degradation complex of β-catenin. AXIN1, found mutated in about 10% of human HCC, has been described as a tumor supressor gene whose loss of function would lead to an aberrant activation of the β-catenin signaling. However, AXIN1-mutated HCC do not belong to the CTNNB1-mutated group. We decided to study the role of Axin1 in liver physiopathology using a mouse model of conditional inactivation that we recently created.

     

     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 Mar 14;11(3):e0150997

    Planchais J, Boutant M, Fauveau V, Qing LD, Sabra-Makke L, Bossard P, Vasseur-Cognet M, Pégorier JP. The role of chicken ovalbumin upstream promoter transcription factor II in the regulation of hepatic fatty acid oxidation and gluconeogenesis in newborn mice. Am J Physiol Endocrinol Metab. 2015 May 15;308(10):E868-78.

    Canal F, Anthony E, Lescure A, Del Nery E, Camonis J, Perez F, Ragazzon B, Perret C. A kinome siRNA screen identifies HGS as a potential target for liver cancers with oncogenic mutations in CTNNB1. BMC Cancer. 2015 Dec 29;15(1):1020.

    Just PA, Poncy A, Charawi S, Dahmani R, Traore M, Dumontet T, Drouet V, Dumont F, Gilgenkrantz H, Colnot S, Terris B, Coulouarn C, Lemaigre F, Perret C. LKB1 and Notch Pathways Interact and Control Biliary Morphogenesis.  PLoS One. 2015 Dec 21;10(12):e0145400.

    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. 2015 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 Apr 30;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 Jun;59(6):2344-57.

    Sabra-Makke L, Maritan M, Planchais J, Boutant M, Pégorier JP, Even PC, Vasseur-Cognet M, Bossard P. Hypothalamic ventromedial COUP-TFII protects against hypoglycemia-associated autonomic failure. Proc Natl Acad Sci U S A. 2013 Mar 12;110(11):4333-8.

    Coulouarn C, Cavard C, Rubbia-Brandt L, Audebourg A, Dumont F, Jacques S, Just PA, Clément B, Gilgenkrantz H, Perret C, Terris B. Combined hepatocellular-cholangiocarcinomas exhibit progenitor features and activation of Wnt and TGFβ signaling pathways. Carcinogenesis. 2012 Sep;33(9):1791-6.

    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.

     

    The group

     

     

    Financial supports

    The project is supported by l’Inserm, la Ligue Nationale Contre le Cancer, l’INCA et l’AFEF.