title: A role for activated Cdc42 in glioblastoma multiforme invasion.
abstract: Cdc42 is a Rho-GTPase which plays a major role in regulating cell polarity and migration by specifying the localization of filopodia. However, the role of Cdc42 in GBM invasion has not been thoroughly investigated. We generated stable doxycycline-inducible clones expressing wild type (WT)-, constitutively active (CA)-, and dominant negative (DN)-Cdc42 in three different human glioma cell lines. Expression of CA-Cdc42 significantly increased the migration and invasive properties of malignant glioma cells compared to WT and DN-Cdc42 cell clones, and this was accompanied by a greater number of filopodia and focal adhesion structures which co-localize with phosphorylated focal adhesion kinase (FAK). By mass spectrometry and immunoprecipitation studies, we demonstrated that activated Cdc42 binds to IQGAP1. When implanted orthotopically in mice, the CA-Cdc42 expressing glioma cells exhibited enhanced local migration and invasion, and led to larger tumors, which significantly reduced survival. Using the Cancer Genome Atlas dataset, we determined that high Cdc42 expression is associated with poorer progression free survival, and that Cdc42 expression is highest in the proneural and neural subgroups of GBM. In summary, our studies demonstrate that activated Cdc42 is a critical determinant of the migratory and invasive phenotype of malignant gliomas, and that its effect may be mediated, at least in part, through its interaction with IQGAP1 and phosphorylated FAK.
authors.affiliation: The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Peter Gilgan Centre for Research and Learning, Toronto, Ontario, M5G 0A4, Canada.|Department of Neurosurgery, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, 113-8342, Japan.
authors.forename: Hidehiro
authors.initials: H
authors.lastname: Okura
authors.affiliation: The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Peter Gilgan Centre for Research and Learning, Toronto, Ontario, M5G 0A4, Canada.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Golbourn
authors.affiliation: The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Peter Gilgan Centre for Research and Learning, Toronto, Ontario, M5G 0A4, Canada.
authors.forename: Uswa
authors.initials: U
authors.lastname: Shahzad
authors.affiliation: The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Peter Gilgan Centre for Research and Learning, Toronto, Ontario, M5G 0A4, Canada.
authors.forename: Sameer
authors.initials: S
authors.lastname: Agnihotri
authors.affiliation: Genetics and Genome Biology, Hospital for Sick Children Research Institute, Toronto, Ontario, M5G 0A4, Canada.
authors.forename: Nesrin
authors.initials: N
authors.lastname: Sabha
authors.affiliation: SPARC Biocentre, The Hospital for Sick Children, Toronto, Ontario, M5G 0A4, Canada.
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Krieger
authors.affiliation: The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Peter Gilgan Centre for Research and Learning, Toronto, Ontario, M5G 0A4, Canada.
authors.forename: Carlyn A
authors.initials: CA
authors.lastname: Figueiredo
authors.affiliation: The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Peter Gilgan Centre for Research and Learning, Toronto, Ontario, M5G 0A4, Canada.
authors.forename: Alan
authors.initials: A
authors.lastname: Chalil
authors.affiliation: The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Peter Gilgan Centre for Research and Learning, Toronto, Ontario, M5G 0A4, Canada.
authors.forename: Natalie
authors.initials: N
authors.lastname: Landon-Brace
authors.affiliation: The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Peter Gilgan Centre for Research and Learning, Toronto, Ontario, M5G 0A4, Canada.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Riemenschneider
authors.affiliation: Department of Neurosurgery, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, 113-8342, Japan.
authors.forename: Hajime
authors.initials: H
authors.lastname: Arai
authors.affiliation: The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Peter Gilgan Centre for Research and Learning, Toronto, Ontario, M5G 0A4, Canada.
authors.forename: Christian A
authors.initials: CA
authors.lastname: Smith
authors.affiliation: Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, Georgia, 30307, USA.
authors.forename: Songli
authors.initials: S
authors.lastname: Xu
authors.affiliation: Department of Neurosurgery, Emory University School of Medicine, Atlanta, Georgia, 30307, USA.|Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, 30307, USA.
authors.forename: Stefan
authors.initials: S
authors.lastname: Kaluz
authors.affiliation: Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, Georgia, 30307, USA.|Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, 30307, USA.
authors.forename: Adam I
authors.initials: AI
authors.lastname: Marcus
authors.affiliation: Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, Georgia, 30307, USA.|Department of Neurosurgery, Emory University School of Medicine, Atlanta, Georgia, 30307, USA.|Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, 30307, USA.
authors.forename: Erwin G
authors.initials: EG
authors.lastname: Van Meir
authors.affiliation: The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Peter Gilgan Centre for Research and Learning, Toronto, Ontario, M5G 0A4, Canada.|Department of Surgery, University of Toronto, Toronto, Ontario, M5T 1P5, Canada.
authors.forename: James T
authors.initials: JT
authors.lastname: Rutka
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D002470:Cell Survival; D018450:Disease Progression; D018572:Disease-Free Survival; D004318:Doxycycline / Q000737:chemistry; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D005799:Genes, Dominant; D005909:Glioblastoma / Q000378:metabolism* / Q000473:pathology; D005910:Glioma / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D010641:Phenotype; D010766:Phosphorylation; D011554:Pseudopodia / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism*; D020703:ras GTPase-Activating Proteins / Q000378:metabolism
chemical_list: C101203:IQ motif containing GTPase activating protein 1; D034741:RNA, Small Interfering; D020703:ras GTPase-Activating Proteins; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D020764:cdc42 GTP-Binding Protein; D004318:Doxycycline
keywords: IQGAP1 and pFAK; cdc42; glioblastoma; invasion; migration