A role for activated Cdc42 in glioblastoma multiforme invasion.
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.
['Okura|Hidehiro|H|', 'Golbourn|Brian J|BJ|', 'Shahzad|Uswa|U|', 'Agnihotri|Sameer|S|', 'Sabha|Nesrin|N|', 'Krieger|Jonathan R|JR|', 'Figueiredo|Carlyn A|CA|', 'Chalil|Alan|A|', 'Landon-Brace|Natalie|N|', 'Riemenschneider|Alexandra|A|', 'Arai|Hajime|H|', 'Smith|Christian A|CA|', 'Xu|Songli|S|', 'Kaluz|Stefan|S|', 'Marcus|Adam I|AI|', 'Van Meir|Erwin G|EG|', 'Rutka|James T|JT|']
D000818:Animals D001932:Brain Neoplasms D002448:Cell Adhesion D045744:Cell Line, Tumor D002465:Cell Movement D002470:Cell Survival D018450:Disease Progression D018572:Disease-Free Survival D004318:Doxycycline D051417:Focal Adhesion Kinase 1 D015972:Gene Expression Regulation, Neoplastic D005799:Genes, Dominant D005909:Glioblastoma D005910:Glioma D006801:Humans D051379:Mice D009361:Neoplasm Invasiveness D009368:Neoplasm Transplantation D010641:Phenotype D010766:Phosphorylation D011554:Pseudopodia D034741:RNA, Small Interfering D020764:cdc42 GTP-Binding Protein D020703:ras GTPase-Activating Proteins
cdc42 glioblastoma invasion migration IQGAP1 and pFAK