Stopping Brain Tumours in Their Tracks- The Role of RhoGTPase Activating Proteins (ARHGAPs) in Glioma Cell Migration and Invasion

Glioblastoma (GBM) is a highly aggressive form of brain cancer that is difficult to treat. Despite efforts to improve treatment outcomes, patients have a median survival of only 12-15 months as tumours will eventually recur leading to patient death. The RhoGTPase activating proteins (ARHGAPs) are a family of proteins that have been associated with various diseases including cancers. A recent microarray screen in the established GBM cell line U251 showed that expression levels of five ARHGAPs significantly changed when exposed to (2'Z,3'E)-6-Bromoindirubin-3'-oxime (BIO), an established migrastatic drug. Of the five ARHGAPs, ARHGAP4, 22 and 25 were investigated here as regulators of cell migration in view of improved treatment options in GBM. Using 2D and 3D migration/invasion assays with established and patient derived cell lines as well as in vivo models and human GBM tissue, the role of ARHGAPs in cell migration and dissemination was investigated. The expression and localisation of ARHGAPs in different GBM subtypes in normoxic and hypoxic conditions were established. Migration studies after gene knockdown in the patient derived cell line G9 revealed that the three ARHGAPs had pro-or-anti-migratory activity. Preliminary in vivo studies with the knockdowns uncovered novel phenotypes after orthoptic intracranial injection leading to tumours with limited migratory activity and highly aggressive tumours. Clinical relevance of the ARHGAPs was determined by an association of ARHGAP expression and survival after treatment. The study's findings enhance our understanding of GBM cell migration, providing potential targets for therapeutic intervention. Overall, the discoveries made represent an important step forward in the development of new treatments for this devastating disease

Preclinical models of glioblastoma:limitations of current models and the promise of new developments

Acknowledgements. The authors thank members of the Speirs group for helpful comments. Financial support. This study was supported by the University of Aberdeen Development Trust and a University of Huddersfield PhD studentship (PV-B).Peer reviewedPostprin