title: Targeting osteopontin suppresses glioblastoma stem-like cell character and tumorigenicity in vivo.
abstract: Osteopontin (OPN) is a secreted protein involved in most aspects of tumor progression and metastasis development. Elevated OPN expression has been reported in multiple types of cancer including glioblastoma (GBM), the highest grade and most aggressive brain tumor. GBMs contain a subpopulation of glioma-initiating cells (GICs) implicated in progression, therapeutic resistance and recurrence. We have previously demonstrated that OPN silencing inhibited GBM cell growth in vitro and in vivo. Moreover, activation of CD44 signaling upon OPN ligation has been recently implicated in the acquisition of a stem cell phenotype by GBM cells. The present study is aimed to explore OPN autocrine function using shRNA silencing strategy in GICs enriched from GBM cell lines and a human primary GBM grown in EGF and bFGF defined medium. The removal of these growth factors and addition of serum induced a significant loss of OPN expression in GICs. We showed that OPN-silenced GICs were unable to grow as spheres and this capacity was restored by exogenous OPN. Importantly, the expression of Sox2, Oct3/4 and Nanog, key stemness transcription factors, was significantly decreased in GICs upon OPN targeting. We identified Akt/mTOR/p70S6K as the main signaling pathway triggered following OPN-mediated EGFR activation in GICs. Finally, in an orthotopic xenograft mouse model, the tumorigenic potential of U87-MG sphere cells was completely abrogated upon OPN silencing. Our demonstration of endogenous OPN major regulatory effects on GICs stemness phenotype and tumorigenicity implies a greater role than anticipated for OPN in GBM pathogenesis from initiation and progression to probable recurrence.
authors.affiliation: Metastasis Research Laboratory, GIGA-Cancer, University of Liège, Belgium.
authors.forename: Virginie
authors.initials: V
authors.lastname: Lamour
authors.affiliation: Metastasis Research Laboratory, GIGA-Cancer, University of Liège, Belgium.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Henry
authors.affiliation: Laboratory of Developmental Neurobiology, GIGA-Neurosciences, University of Liège, Belgium.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Kroonen
authors.affiliation: Metastasis Research Laboratory, GIGA-Cancer, University of Liège, Belgium.
authors.forename: Marie-Julie
authors.initials: MJ
authors.lastname: Nokin
authors.affiliation: Craniofacial and Skeletal Diseases Branch, NIDCR, NIH, DHHS, Bethesda, MD.
authors.forename: Zofia
authors.initials: Z
authors.lastname: von Marschall
authors.affiliation: Craniofacial and Skeletal Diseases Branch, NIDCR, NIH, DHHS, Bethesda, MD.
authors.forename: Larry W
authors.initials: LW
authors.lastname: Fisher
authors.affiliation: Laboratory of Medical Chemistry, GIGA-Signal Transduction, University of Liège, Belgium.
authors.forename: Tieu-Lan
authors.initials: TL
authors.lastname: Chau
authors.affiliation: Laboratory of Medical Chemistry, GIGA-Signal Transduction, University of Liège, Belgium.
authors.forename: Alain
authors.initials: A
authors.lastname: Chariot
authors.affiliation: UMR 975, INSERM-UPMC, GH Pitié-Salpêtrière, Paris.
authors.forename: Marc
authors.initials: M
authors.lastname: Sanson
authors.affiliation: UMR 975, INSERM-UPMC, GH Pitié-Salpêtrière, Paris.
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Delattre
authors.affiliation: Metastasis Research Laboratory, GIGA-Cancer, University of Liège, Belgium.
authors.forename: Andrei
authors.initials: A
authors.lastname: Turtoi
authors.affiliation: Metastasis Research Laboratory, GIGA-Cancer, University of Liège, Belgium.
authors.forename: Olivier
authors.initials: O
authors.lastname: Peulen
authors.affiliation: Laboratory of Developmental Neurobiology, GIGA-Neurosciences, University of Liège, Belgium.|Stem Cells and Regenerative Medicine, GIGA-Development, University of Liège, Belgium.
authors.forename: Bernard
authors.initials: B
authors.lastname: Rogister
authors.affiliation: Metastasis Research Laboratory, GIGA-Cancer, University of Liège, Belgium.
authors.forename: Vincent
authors.initials: V
authors.lastname: Castronovo
authors.affiliation: Metastasis Research Laboratory, GIGA-Cancer, University of Liège, Belgium.
authors.forename: Akeila
authors.initials: A
authors.lastname: Bellahcène
mesh_terms: D000818:Animals; D019898:Autocrine Communication; D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D020868:Gene Silencing; D005909:Glioblastoma / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000502:physiology*; D053495:Osteopontin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D018874:Spheroids, Cellular / Q000378:metabolism
chemical_list: D034741:RNA, Small Interfering; D053495:Osteopontin
keywords: EGFR; Sox2; glioblastoma; osteopontin; tumor initiating cells