title: The Cytoskeletal Adapter Protein Spinophilin Regulates Invadopodia Dynamics and Tumor Cell Invasion in Glioblastoma.
abstract: Glioblastoma is a primary brain cancer that is resistant to all treatment modalities. This resistance is due, in large part, to invasive cancer cells that disperse from the main tumor site, escape surgical resection, and contribute to recurrent secondary lesions. The adhesion and signaling mechanisms that drive glioblastoma cell invasion remain enigmatic, and as a result there are no effective anti-invasive clinical therapies. Here we have characterized a novel adhesion and signaling pathway comprised of the integrin αvβ8 and its intracellular binding partner, Spinophilin (Spn), which regulates glioblastoma cell invasion in the brain microenvironment. We show for the first time that Spn binds directly to the cytoplasmic domain of β8 integrin in glioblastoma cells. Genetically targeting Spn leads to enhanced invasive cell growth in preclinical models of glioblastoma. Spn regulates glioblastoma cell invasion by modulating the formation and dissolution of invadopodia. Spn-regulated invadopodia dynamics are dependent, in part, on proper spatiotemporal activation of the Rac1 GTPase. Glioblastoma cells that lack Spn showed diminished Rac1 activities, increased numbers of invadopodia, and enhanced extracellular matrix degradation. Collectively, these data identify Spn as a critical adhesion and signaling protein that is essential for modulating glioblastoma cell invasion in the brain microenvironment.
  
  
  
  Tumor cell invasion is a major clinical obstacle in glioblastoma and this study identifies a new signaling pathway regulated by Spinophilin in invasive glioblastoma. Mol Cancer Res; 14(12); 1277-87. ©2016 AACR.
authors.affiliation: University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Mujeeburahiman
authors.initials: M
authors.lastname: Cheerathodi
authors.affiliation: University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Naze G
authors.initials: NG
authors.lastname: Avci
authors.affiliation: University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Paola A
authors.initials: PA
authors.lastname: Guerrero
authors.affiliation: Texas A&M University, College Station, Texas.
authors.forename: Leung K
authors.initials: LK
authors.lastname: Tang
authors.affiliation: Texas A&M University, College Station, Texas.
authors.forename: Julia
authors.initials: J
authors.lastname: Popp
authors.affiliation: University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: John E
authors.initials: JE
authors.lastname: Morales
authors.affiliation: University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Spanish National Research Council, Madrid, Spain.
authors.forename: Amancio
authors.initials: A
authors.lastname: Carnero
authors.affiliation: University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Frederick F
authors.initials: FF
authors.lastname: Lang
authors.affiliation: University of Vermont, Burlington, Vermont.
authors.forename: Bryan A
authors.initials: BA
authors.lastname: Ballif
authors.affiliation: Texas A&M University, College Station, Texas.
authors.forename: Gonzalo M
authors.initials: GM
authors.lastname: Rivera
authors.affiliation: University of Texas MD Anderson Cancer Center, Houston, Texas. jhmccarty@mdanderson.org.
authors.forename: Joseph H
authors.initials: JH
authors.lastname: McCarty
mesh_terms: D000818:Animals; D001665:Binding Sites; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology*; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D016023:Integrins / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D008840:Microfilament Proteins / Q000737:chemistry / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000378:metabolism*; D000069261:Podosomes / Q000378:metabolism*; D011485:Protein Binding; D015398:Signal Transduction; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*; D000099273:Neurabins
chemical_list: D016023:Integrins; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; D020830:rac1 GTP-Binding Protein; D000099273:Neurabins; C107953:RAC1 protein, human; C403414:integrin alphavbeta8