AccueilAccueil>La recherche>Teams>Sabine COLNOT

Oncogenic funtions of beta-catenin
signaling in the liver

  

Objectives
Primary liver cancer is the second cause of death related to cancer worldwide. Our objective is to unravel the sequence of the genetic and epigenetic events driving liver carcinogenesis, to open the way to new diagnostic and therapeutic opportunities. We are focusing in particular on liver carcinogenesis dependent on the Wnt/β-catenin pathway, found aberrantly activated by mutations in one third of hepatocellular carcinomas (HCC) in patients. In that respect, we have engineered genetically-modified mice such as the Apcko model (Colnot, PNAS 2004), to study this type of HCC and we are currently using the CRISPR/Cas9 strategy to create new models of HCC.

 

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), related to its role in liver zonation (Benhamouche, Dev Cell 2016). This transcription is aberrantly activated in liver cancers, together with the appearance of new oncogenic targets (Torre, J Hepatol 2011 ; Gougelet, Hepatology 2014). 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 (insulin receptor, glutamine synthetase, TCF-4, the DLK1/DIO3 locus…).

 

Team Leader: Sabine COLNOT (DR2; Inserm)

 

Team Members:

Researchers: Christèle DESBOIS-MOUTHON (CR; Inserm), Angélique GOUGELET (CR; Inserm) 

Technical Staff: Cécile GODARD (IE; Inserm)

Young Researchers: Julie SANCEAU (PhD Student), Robin LOESCH (PhD Student)

 

  

Publications

  • Exosomal microRNAs as a potential therapeutic strategy in hepatocellular carcinoma. Gougelet A.  World J Hepatol. 2018 Nov 27 ;10(11) :785-789. doi : 10.4254/wjh.v10.i11.785.
  • Epigenetic modulation of immunity: towards new therapeutic avenues in hepatocellular carcinoma?. Gougelet A. Gut. 2019 Jun 26. pii: gutjnl-2019-319084. doi: 10.1136/gutjnl-2019-319084.
  • Hepatocellular Carcinomas With Mutational Activation of Beta Catenin Require Choline and can be Detected by Positron Emission Tomography.
    Gougelet A, Sartor C, Senni N, Calderaro J, Fartoux L, Lequoy M, Wendum D, Talbot JN, Prignon A, Chalaye J, Imbeaud S, Zucman-Rossi J, Tordjmann T, Godard C, Bossard P, Rosmorduc O, Amaddeo G, Colnot S. Gastroenterology. 2019 Jun 10. pii: S0016-5085(19)40988-8. doi: 10.1053/j.gastro.2019.05.069. PMID:31194980 
  • Insulin receptor isoform A favors tumor progression in human hepatocellular carcinoma by increasing stem/progenitor cell features. Benabou E, Salamé Z, Wendum D, Lequoy M, Tahraoui S, Merabtene F, Chrétien Y, Scatton O, Rosmorduc O, Fouassier L, Fartoux L, Praz F, Desbois-Mouthon C. Cancer Lett. 2019 Mar 5. pii: S0304-3835(19)30123-5. doi: 10.1016/j.canlet.2019.02.037. PMID: 30849481
  • The concomitant loss of APC and HNF4α in adult hepatocytes does not contribute to hepatocarcinogenesis driven by β-catenin activation. Sartor C, Bachelot L, Godard C, Lager F, Renault G, Gonzalez FJ, Perret C, Gougelet A, Colnot S. Liver Int. 2019 Feb 5. doi: 10.1111/liv.14068. PMID: 30721564
  • Loesch, R., Desbois-Mouthon, C., and Colnot, S. Potentials of CRISPR in liver research and therapy. Clin Res Hepatol Gastroenterol. 2018
  • Meakin P., Mezzapesa A., Benabou E., Haas M.E, Bonardo B., Grino M., Desbois-Mouthon C., Biddinger B.S, Govers R., Ashford M., Peiretti F.The beta secretase BACE1 regulates the expression of the insulin receptor in the liver. Nature Communications, 2018 3;9(1):1306
  • 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.
  • Buta, C., Benabou, E., Lequoy, M., Regnault, H., Wendum, D., Meratbene, F., Chettouh, H., Aoudjehane, L., Conti, F., Chretien, Y., Scatton, O., Rosmorduc, O., Praz, F., Fartoux, L., and Desbois-Mouthon, C. Heregulin-1beta and HER3 in hepatocellular carcinoma: status and regulation by insulin. J Exp Clin Cancer Res 2016 35, 126
  • 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.
  • Chettouh, H., Fartoux, L., Aoudjehane, L., Wendum, D., Claperon, A., Chretien, Y., Rey, C., Scatton, O., Soubrane, O., Conti, F., Praz, F., Housset, C., Rosmorduc, O., Desbois-Mouthon, C. Mitogenic insulin receptor-A is overexpressed in human hepatocellular carcinoma due to EGFR-mediated dysregulation of RNA splicing factors. Cancer Res 2013 73, 3974-3986.
  • 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. Epub 2004 Nov 24.

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Financial supports
These programs are supported by INSERM, Ligue Nationale Contre le Cancer (LNCC), Fondation ARC, SIRIC CARPEM, Institut du Cancer (INCa), Plan Cancer and ANR.

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