title: Cellular plasticity confers migratory and invasive advantages to a population of glioblastoma-initiating cells that infiltrate peritumoral tissue.
abstract: Glioblastoma (GBM) is associated with infiltration of peritumoral (PT) parenchyma by isolated tumor cells that leads to tumor regrowth. Recently, GBM stem-like or initiating cells (GICs) have been identified in the PT area, but whether these GICs have enhanced migratory and invasive capabilities compared with GICs from the tumor mass (TM) is presently unknown. We isolated GICs from the infiltrated PT tissue and the TM of three patients and found that PT cells have an advantage over TM cells in two-dimensional and three-dimensional migration and invasion assays. Interestingly, PT cells display a high plasticity in protrusion formation and cell shape and their migration is insensitive to substrate stiffness, which represent advantages to infiltrate microenvironments of different rigidity. Furthermore, mouse and chicken embryo xenografts revealed that only PT cells showed a dispersed distribution pattern, closely associated to blood vessels. Consistent with cellular plasticity, simultaneous Rac and RhoA activation are required for the enhanced invasive capacity of PT cells. Moreover, Rho GTPase signaling modulators αVβ3 and p27 play key roles in GIC invasiveness. Of note, p27 is upregulated in TM cells and inhibits RhoA activity. Gene silencing of p27 increased the invasive capacity of TM GICs. Additionally, β3 integrin is upregulated in PT cells. Blockade of dimeric integrin αVβ3, a Rac activator, reduced the invasive capacity of PT GICs in vitro and abrogated the spreading of PT cells into chicken embryos. Thus, our results describe the invasive features acquired by a unique subpopulation of GICs that infiltrate neighboring tissue.
authors: Molecular Genetics Unit, Hospital Universitario Marqués de Valdecilla and Instituto de Formación e Investigación Marques de Valdecilla (IFIMAV), Av. Cardenal Herrera Oria s/n, Santander, Spain.
authors: Patricia
authors: P
authors: Ruiz-Ontañon
authors: Jose L
authors: JL
authors: Orgaz
authors: Beatriz
authors: B
authors: Aldaz
authors: Alberto
authors: A
authors: Elosegui-Artola
authors: Juan
authors: J
authors: Martino
authors: Maria T
authors: MT
authors: Berciano
authors: Juan A
authors: JA
authors: Montero
authors: Lara
authors: L
authors: Grande
authors: Lorena
authors: L
authors: Nogueira
authors: Santiago
authors: S
authors: Diaz-Moralli
authors: Azucena
authors: A
authors: Esparís-Ogando
authors: Alfonso
authors: A
authors: Vazquez-Barquero
authors: Miguel
authors: M
authors: Lafarga
authors: Atanasio
authors: A
authors: Pandiella
authors: Marta
authors: M
authors: Cascante
authors: Victor
authors: V
authors: Segura
authors: Jose A
authors: JA
authors: Martinez-Climent
authors: Victoria
authors: V
authors: Sanz-Moreno
authors: Jose L
authors: JL
authors: Fernandez-Luna
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics / Q000502:physiology*; D002642:Chick Embryo; D015536:Down-Regulation; D005260:Female; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D064593:Heterografts; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009361:Neoplasm Invasiveness; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D020744:rac GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D039302:Integrin alphaVbeta3; D020744:rac GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein