title: Fibronectin expression in glioblastomas promotes cell cohesion, collective invasion of basement membrane in vitro and orthotopic tumor growth in mice.
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.
authors.affiliation: 1] Université de Nice-Sophia Antipolis, Nice, France [2] Institut de Biologie Valrose, CNRS UMR7277-INSERM U1091, Nice, France.
authors.forename: E
authors.initials: E
authors.lastname: Serres
authors.affiliation: Aix-Marseille Université, IBDML, CNRS UMR7288, Marseille, France.
authors.forename: F
authors.initials: F
authors.lastname: Debarbieux
authors.affiliation: Aix-Marseille Université, IBDML, CNRS UMR7288, Marseille, France.
authors.forename: F
authors.initials: F
authors.lastname: Stanchi
authors.affiliation: Université de Nice-Sophia Antipolis, Nice, France.
authors.forename: L
authors.initials: L
authors.lastname: Maggiorella
authors.affiliation: 1] Université de Nice-Sophia Antipolis, Nice, France [2] Institut de Biologie Valrose, CNRS UMR7277-INSERM U1091, Nice, France.
authors.forename: D
authors.initials: D
authors.lastname: Grall
authors.affiliation: 1] Université de Nice-Sophia Antipolis, Nice, France [2] Institut de Biologie Valrose, CNRS UMR7277-INSERM U1091, Nice, France.
authors.forename: L
authors.initials: L
authors.lastname: Turchi
authors.affiliation: 1] Université de Nice-Sophia Antipolis, Nice, France [2] Institut de Biologie Valrose, CNRS UMR7277-INSERM U1091, Nice, France [3] Service d'Anatomopathologie, Hôpital Pasteur, CHU de Nice, Nice, France.
authors.forename: F
authors.initials: F
authors.lastname: Burel-Vandenbos
authors.affiliation: Aix-Marseille Université, INSERM UMR911, Marseille, France.
authors.forename: D
authors.initials: D
authors.lastname: Figarella-Branger
authors.affiliation: 1] Université de Nice-Sophia Antipolis, Nice, France [2] Institut de Biologie Valrose, CNRS UMR7277-INSERM U1091, Nice, France.
authors.forename: T
authors.initials: T
authors.lastname: Virolle
authors.affiliation: Aix-Marseille Université, IBDML, CNRS UMR7288, Marseille, France.
authors.forename: G
authors.initials: G
authors.lastname: Rougon
authors.affiliation: 1] Université de Nice-Sophia Antipolis, Nice, France [2] Institut de Biologie Valrose, CNRS UMR7277-INSERM U1091, Nice, France.
authors.forename: E
authors.initials: E
authors.lastname: Van Obberghen-Schilling
mesh_terms: D000818:Animals; D001485:Basement Membrane / Q000166:cytology; D002448:Cell Adhesion / Q000235:genetics*; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D005109:Extracellular Matrix; D005353:Fibronectins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D006801:Humans; D039081:Integrin alpha5beta1 / Q000378:metabolism; D051379:Mice; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic / Q000235:genetics; D020033:Protein Isoforms / Q000096:biosynthesis / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering; D018874:Spheroids, Cellular; D014407:Tumor Cells, Cultured
chemical_list: D005353:Fibronectins; D039081:Integrin alpha5beta1; D020033:Protein Isoforms; D034741:RNA, Small Interfering