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Author Notes:

Correspondence to:James T. Rutka,Email: james.rutka@sickkids.ca

No conflicts of interest.

Subjects:

Research Funding:

This work was supported by grants from Canadian Institute of Health Research (MOP 74610), and by funds from b.r.a.i.n.child, Meagan's Walk (Meagan Bebenek Research Institute), and Laurie Berman and Wiley Family funds for brain tumour research.

This work was partially supported by the National Cancer Institute (CA1428580 to AIM, and CA86335, CA163722 to EGVM).

Research reported in this publication was supported in part by the Winship and Emory Integrated Cellular Imaging Core and NIH/NCI under award number P30CA138292.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Oncology
  • Cell Biology
  • cdc42
  • glioblastoma
  • migration
  • invasion
  • IQGAP1 and pFAK
  • FOCAL ADHESION KINASE
  • GLIOMA-CELL INVASION
  • RHO-GTPASES
  • ANAPLASTIC ASTROCYTOMA
  • CANCER-CELLS
  • IN-VIVO
  • MIGRATION
  • IQGAP1
  • PROLIFERATION
  • PATHWAY

A role for activated Cdc42 in glioblastoma multiforme invasion

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Journal Title:

Oncotarget

Volume:

Volume 7, Number 35

Publisher:

, Pages 56958-56975

Type of Work:

Article | Final Publisher PDF

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 doxycyclineinducible clones expressing wild type (WT)-, constitutively active (CA)-, and dominant negative (DN)-Cdc42 in three different human glioma cell lines. Expression of CACdc42 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.

Copyright information:

© 2016 Okura et al.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 3.0 Unported License (http://creativecommons.org/licenses/by/3.0/).

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