Cell/cell and cell/matrix adhesion in the regulation of tumour-initiating cells

Project Details

Our lab is interested in the characterisation of signalling pathways that are differentially activated in Cancer Stem Cells (CSCs) from colorectal cancer, and to determine how the effects of intrinsic and environmental factors combine to regulate these pathways.  We aim to characterise these regulators using integrated in vivo models of tumour progression and treatment response.

Among extrinsic regulators of cell phenotype, protein complexes involved in direct contacts between tumour and neighbouring cells have been shown to play an instrumental role in controlling the phenotype of CSCs. Claudin-2, an adhesion protein that is overexpressed in primary and metastatic human colorectal cancer (CRC), exerts tumour-promoting activities in vitro, and our results support the hypothesis that claudin-2 regulates self-renewal, a characteristic phenotypic trait of TICs.  We are exploring the molecular mechanisms underlying this effect and analysing the regulatory role of claudin-2 on metastasis development and tumour relapse, two other processes where TIC involvement has been demonstrated.

In addition, extracellular matrix (ECM) proteins have emerged as important regulators of tumour progression and epithelial to mesenchyme transition (EMT), a program that has been shown to promote stemness characteristics in cancer cells. We are exploring the relationship between stemness and EMT during metastasis development, and we are particularly interested in the role of laminins in this process and in the impact of this family of proteins on the cancer stem cell phenotype.

Researchers

Dr Sophie Paquet-Fifield (PhD), Post-doctoral Research fellow (NH&MRC)
Ms. Laura Marie Failla, Research Assistant
Ms Yan (Doris) Qin, PhD student

Collaborators

National

A/Prof Mathias Ernst/Dr. Michael Buchert - Olivia Newton-John Cancer Research Institute (ONJCRI)
Dr. Erica Sloan - Monash Institute of Pharmaceutical Sciences, Monash University
Professor Andrew Hill, Department of Biochemistry and Genetics, La Trobe University, Melbourne

International

Assoc Prof Sergei Rodin, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
Prof Jean-Paul Thiery, A*STAR Institute of Molecular and Cellular Biology, Singapore

Funding

National Health and Medical Research Council of Australia (NHMRC) Project grant: "Role of claudin-2 on the development of colorectal cancer metastases and their resistance to treatment"

University of Melbourne Department of Pathology.

Research Publications

  • Arsic N., Gadea G., Lagerqvist EL., Busson M., Cahuzac N., Brock C., Hollande F., Gire V., Pannequin J. and Roux P. The p53 Isoform D133p53b Promotes Cancer Stem Cell Potential. Stem Cell Reports 2015; http://dx.doi.org/10.1016/j.stemcr.2015.02.001
  • Bonnans C, Flacelière M, Grillet F, Dantec C, Desvignes JP, Pannequin J, Severac D, Dubois E, Bibeau F, Escriou V, Crespy P, Journot L, Hollande F* and Joubert D*. Essential requirement for β-arrestin2 in mouse intestinal tumors with elevated Wnt signaling. (*Joint supervising authors). Proc Natl Acad Sci USA 2012 Feb 21;109(8): 3047-52.
  • Buchert M., Turksen K. and Hollande F. Methods to examine tight junction physiology in cancer stem cells: TEER, paracellular permeability, and dilution potential measurements. Stem Cell Rev 2012 Sep;8(3): 1030-4.
  • Hollande F., Pannequin J., and Joubert D. (2010) The long road to colorectal cancer therapy: searching for the right signals. Drug Resistance Updates 2010 Feb-Apr;13(1-2): 44-56.
  • Buchert M, Papin M, Bonnans C, Darido C, Raye WS, Garambois V, Pélegrin A, Bourgaux JF, Pannequin J, Joubert D, and Hollande F. (2010) Symplekin promotes tumorigenicity by upregulating claudin-2 expression. Proc. Nat. Acad Sci USA, 2010 Feb 9;107(6): 2628-33.
  • Diouf B, Collazos A, Labesse G, Macari F, Choquet A, Clair P, Gauthier-Rouvière C, Guérineau NC, Jay P, Hollande, F.*, and Joubert D*.  A 20-Amino Acid Module of Protein Kinase C{epsilon} Involved in Translocation and Selective Targeting at Cell-Cell Contacts. J Biol Chem 2009;284(28): 18808-15 (*Joint supervising authors).
  • Michael Buchert, Charbel Darido, Ebba Lagerqvist, Anna Sedello, Chantal Cazevieille, Frank Buchholz, Julie Pannequin, Dominique Joubert and Frédéric Hollande. AML1/Runx1 is an essential intermediate in the modulation of intestinal cell differentiation by the symplekin/ZONAB complex. Gastroenterology 2009;137(1): 156-64, 164.e1-3.
  • Charbel Darido, Michael Buchert, Julie Pannequin, Pauline Bastide, Hassan Zalzali, Theo Mantamadiotis, Jean-François Bourgaux, Véronique Garambois, Philippe Jay, Philippe Blache, Dominique Joubert, and Frédéric Hollande. Defective claudin-7 regulation by Tcf-4 and Sox-9 disrupts the polarity and increases the tumorigenicity of colorectal cancer cells. Cancer Res 2008 Jun 1;68(11): 4258-68.
  • Research Group

    Hollande laboratory: Molecular mechanisms of tumour progression



    Faculty Research Themes

    Cancer

    School Research Themes

    Cancer in Biomedicine, Molecular Mechanisms of Disease, Stem Cells



    Key Contact

    For further information about this research, please contact the research group leader.

    Department / Centre

    Pathology