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    New targets of beta-catenin in primary liver cancers

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    Principal Investigator: Sabine Colnot DR2 INSERM
    CV science avesan

     

    Objective

    Primary liver cancer is the second cause of death by cancer worldwide. Our objective is to better understand the sequence of genetic and epigenetic events driving this carcinogenesis, as a key to open the way to new therapeutic avenues. In that respect, we engineer genetically-modified mice such as the Apcko model (Colnot, PNAS 2004), to study liver carcinogenesis linked to β-catenin aberrant signaling, found activated through mutations in one third of hepatocellular carcinomas in humans.

     

    Research interests

    1/ MECHANISMS AND CONSEQUENCES OF β-CATENIN-DEPENDENT TRANSCRIPTION IN LIVER CANCERS. Our recent data have shown that β-catenin drives in the liver a metabolism-directed transcription (Gougelet, Hepatology 2014), which is the source of its role in liver zonation (Benhamouche, Dev Cell 2006). This transcription is aberrantly activated in liver cancers, together with the appearance of new oncogenic targets (Gougelet, Hepatology 2014 ; Torre, J Hepatol 2011). We will search for the epigenetic hallmarks , which regulate these transcriptional programs, and for the targets responsible for liver carcinogenesis.

     2/ ONCOGENIC COOPERATIONS & EPIGENETIC ACTORS. Recent data from whole-exome sequencing of human liver tumors pointed towards new mutations, involving new oncogenes and tumor suppressors. We will assess in vivo in mice the role of these new mutations in cooperation with those affecting β-catenin, focusing on mutated epigenetic players.

     3/ EMERGENT THERAPEUTIC AVENUES. We have recently proposed a therapeutic strategy specific for β-catenin-activated liver cancers, and based on miRNAs (Gougelet, Gut 2016). The genetically-modified mice that we generate will be used to test in vivo therapies based on our most relevant targets.

     

    Main publications

    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 65(6):1024-34.

    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. Hepatology. 2014 Jun;59(6):2344-57.

    Torre C, Benhamouche S, Mitchell C, Godard C, Veber P, Letourneur F, Cagnard N, Jacques S, Finzi L, Perret C, Colnot S. The transforming growth factor-α and cyclin D1 genes are direct targets of β-catenin signaling in hepatocyte proliferation. J Hepatol. 2011 Jul;55(1):86-95.

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

    Benhamouche S, Decaens T, Godard C, Chambrey R, Rickman DS, Moinard C, Vasseur-Cognet M, Kuo CJ, Kahn A, Perret C, Colnot S. Apc tumor suppressor gene is the "zonation-keeper" of mouse liver. Dev Cell. 2006 Jun;10(6):759-70.

    Colnot S, Decaens T, Niwa-Kawakita M, Godard C, Hamard G, Kahn A, Giovannini M, Perret C. Liver-targeted disruption of Apc in mice activates β-catenin signaling and leads to hepatocellular carcinomas. Proc Natl Acad Sci U S A. 2004 Dec 7;101(49):17216-21.

     

    The group

     

     

     

     

     

    Financial supports

    These programs are supported by INSERM, Ligue Nationale Contre le Cancer (LNCC), Labex « Who Am I », Institut du Cancer (INCa), Plan Cancer.