A role for activated Cdc42 in glioblastoma multiforme invasion
Bibliographic record
Abstract
// Hidehiro Okura 1, 2 , Brian J. Golbourn 1 , Uswa Shahzad 1 , Sameer Agnihotri 1 , Nesrin Sabha 7 , Jonathan R. Krieger 8 , Carlyn A. Figueiredo 1 , Alan Chalil 1 , Natalie Landon-Brace 1 , Alexandra Riemenschneider 1 , Hajime Arai 2 , Christian A. Smith 1 , Songli Xu 5 , Stefan Kaluz 4, 6 , Adam I. Marcus 5, 6 , Erwin G. Van Meir 4, 5, 6 , James T. Rutka 1, 3 1 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 2 Department of Neurosurgery, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan 3 Department of Surgery, University of Toronto, Toronto, Ontario, M5T 1P5, Canada 4 Department of Neurosurgery, Emory University School of Medicine, Atlanta, Georgia, 30307, USA 5 Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta Georgia, 30307, USA 6 Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, 30307, USA 7 Genetics and Genome Biology, Hospital for Sick Children Research Institute, Toronto, Ontario, M5G 0A4, Canada 8 SPARC Biocentre, The Hospital for Sick Children, Toronto, Ontario, M5G 0A4, Canada Correspondence to: James T. Rutka, email: james.rutka@sickkids.ca Keywords: cdc42, glioblastoma, migration, invasion, IQGAP1 and pFAK Received: February 02, 2016     Accepted: July 18, 2016     Published: July 29, 2016 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.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".