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Fibronectin expression in glioblastomas promotes cell cohesion, collective invasion of basement membrane in vitro and orthotopic tumor growth in mice

Oncogene volume 33, pages 3451–3462 (2014)Cite this article

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Abstract

Glioblastoma multiforme (GBM) are highly invasive and angiogenic malignancies with a median survival time from diagnosis of <15 months. Previous work has revealed robust overexpression of fibronectin (FN) mRNA in GBM, although immunohistochemical staining of FN in these tumors is typically associated with the angiogenic vasculature. Here we sought to examine the expression of tumor cell FN and address its possible involvement in the invasive phenotype of GBM. We found that FN was expressed and assembled into fibrillar arrays in human tumors and in established GBM lines. Cultured cells spontaneously formed dense cellular networks and spheroid-like domes. Depletion of FN by targeted-short hairpin RNA expression disrupted matrix assembly and multicellular network organization by exerting profound effects on cell adhesion and motility. Although FN depletion enhanced persistent directional migration of single cells, it compromised collective invasion of spheroids through a laminin-rich matrix and sensitized cells to ionizing radiation. In orthotopic grafts, FN depletion significantly reduced tumor growth and angiogenesis. Together our results show that FN produced by the tumor cells has a role in GBM pathophysiology and they provide insights into the implications that targeting FN interactions may have for combating this dreaded disease.

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Acknowledgements

We thank Jean-François Michiels and Philippe Paquis (Pathology and Neurosurgery Departments of the Nice CHU) for their collaboration. We also thank Botond Cseh, Nathalie Baeza-Kallee, Clément Ricard, Sandeep Gopal and Juliette Thariat for valuable discussions, cell lines, help with intracranial xenograft experiments and statistical analyses. Patrick Stern and Richard Hynes are kindly acknowledged for providing the lentiviral vector, Aurélie Rossin for assistance with cytometry, Sebastien Schaub (PRISM Platform, CNRS-UMR6543) and the PICSIL Platform (CNRS-6216) for expert help with image analyses. Serge Marcie and Jean-Louis Fischel (Centre A. Lacassagne) are gratefully acknowledged for helping with irradiation experiments, and Arnaud Borderie, Sandrine Destree, Coralie Hagnere et Bérengère Szczépaniak for immunohistochemistry. Financial support for this work was provided by the French National Institute of Cancer (INCa, RS018), the French Association of Cancer Research (ARC 4965 to EVO-S and 5095 to GR), the National Agency for Research (JCC PathoVisu3dyn to FD), la Fondation de Recherche sur le Cerveau to FD, Canceropole PACA and l’Agence Nationale pour la Recherche (ANR Jeunes Chercheurs, ‘GLIOMIRSTEM’ to TV).

Author information

Author notes

  1. F Stanchi

    Present address: 7Current address: Vesalius Research Center, Leuven, Belgium.,

  2. L Maggiorella

    Present address: 8Current address: Nanobiotix, 60 Rue de Wattignies, 75012 Paris, France.,

  3. F Debarbieux and F Stanchi: These authors contributed equally to this study.

Authors and Affiliations

  1. Université de Nice-Sophia Antipolis, Nice, France

    E Serres, L Maggiorella, D Grall, L Turchi, F Burel-Vandenbos, T Virolle & E Van Obberghen-Schilling

  2. Institut de Biologie Valrose, CNRS UMR7277–INSERM U1091, Nice, France

    E Serres, D Grall, L Turchi, F Burel-Vandenbos, T Virolle & E Van Obberghen-Schilling

  3. Aix-Marseille Université, IBDML, CNRS UMR7288, Marseille, France

    F Debarbieux, F Stanchi & G Rougon

  4. Service d′Anatomopathologie, Hôpital Pasteur, CHU de Nice, Nice, France

    F Burel-Vandenbos

  5. Aix-Marseille Université, INSERM UMR911, Marseille, France

    D Figarella-Branger

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Correspondence to E Van Obberghen-Schilling.

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Serres, E., Debarbieux, F., Stanchi, F. et al. Fibronectin expression in glioblastomas promotes cell cohesion, collective invasion of basement membrane in vitro and orthotopic tumor growth in mice. Oncogene 33, 3451–3462 (2014). https://doi.org/10.1038/onc.2013.305

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