GBM heterogeneity as a function of variable epidermal growth factor receptor variant III activity
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Olle R. Lindberg1, Andrew McKinney1, Jane R. Engler1, Gayane Koshkakaryan2, Henry Gong1, Aaron E. Robinson1, Andrew J. Ewald3, Emmanuelle Huillard4, C. David James5, Annette M. Molinaro1,6,7, Joseph T. Shieh8, Joanna J. Phillips1,6,9
1Department of Neurological Surgery, Brain Tumor Center, University of California, San Francisco, CA, USA
2Touro University California, College of Osteopathic Medicine. Vallejo, CA, USA
3Departments of Cell Biology, Oncology, and Biomedical Engineering, School of Medicine, Johns Hopkins University, Baltimore, MD, USA
4Université Pierre et Marie Curie (UPMC) UMR-S975, Inserm U1127, CNRS UMR7225, Institut du Cerveau et de la Moelle Epiniere, Paris, France
5Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
6Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA
7Epidemiology and Biostatistics, University of California, San Francisco, CA, USA
8Institute for Human Genetics, Department of Pediatrics, University of California, San Francisco, CA, USA
9Department of Pathology, Division of Neuropathology, University of California, San Francisco, CA, USA
Joanna J. Phillips, email: Joanna.email@example.com
Keywords: RTK activity, extracellular matrix, tumor heterogeneity, vessel co-option, invasion
Received: August 06, 2016 Accepted: September 29, 2016 Published: October 12, 2016
Abnormal activation of the epidermal growth factor receptor (EGFR) due to a deletion of exons 2-7 of EGFR (EGFRvIII) is a common alteration in glioblastoma (GBM). While this alteration can drive gliomagenesis, tumors harboring EGFRvIII are heterogeneous. To investigate the role for EGFRvIII activation in tumor phenotype we used a neural progenitor cell-based murine model of GBM driven by EGFR signaling and generated tumor progenitor cells with high and low EGFRvIII activation, pEGFRHi and pEGFRLo. In vivo, ex vivo, and in vitro studies suggested a direct association between EGFRvIII activity and increased tumor cell proliferation, decreased tumor cell adhesion to the extracellular matrix, and altered progenitor cell phenotype. Time-lapse confocal imaging of tumor cells in brain slice cultures demonstrated blood vessel co-option by tumor cells and highlighted differences in invasive pattern. Inhibition of EGFR signaling in pEGFRHi promoted cell differentiation and increased cell-matrix adhesion. Conversely, increased EGFRvIII activation in pEGFRLo reduced cell-matrix adhesion. Our study using a murine model for GBM driven by a single genetic driver, suggests differences in EGFR activation contribute to tumor heterogeneity and aggressiveness.
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