title: GBM heterogeneity as a function of variable epidermal growth factor receptor variant III activity.
abstract: 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.
authors.affiliation: Department of Neurological Surgery, Brain Tumor Center, University of California, San Francisco, CA, USA.
authors.forename: Olle R
authors.initials: OR
authors.lastname: Lindberg
authors.affiliation: Department of Neurological Surgery, Brain Tumor Center, University of California, San Francisco, CA, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: McKinney
authors.affiliation: Department of Neurological Surgery, Brain Tumor Center, University of California, San Francisco, CA, USA.
authors.forename: Jane R
authors.initials: JR
authors.lastname: Engler
authors.affiliation: Touro University California, College of Osteopathic Medicine, Vallejo, CA, USA.
authors.forename: Gayane
authors.initials: G
authors.lastname: Koshkakaryan
authors.affiliation: Department of Neurological Surgery, Brain Tumor Center, University of California, San Francisco, CA, USA.
authors.forename: Henry
authors.initials: H
authors.lastname: Gong
authors.affiliation: Department of Neurological Surgery, Brain Tumor Center, University of California, San Francisco, CA, USA.
authors.forename: Aaron E
authors.initials: AE
authors.lastname: Robinson
authors.affiliation: Departments of Cell Biology, Oncology, and Biomedical Engineering, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Ewald
authors.affiliation: Université Pierre et Marie Curie (UPMC) UMR-S975, Inserm U1127, CNRS UMR7225, Institut du Cerveau et de la Moelle Epiniere, Paris, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Huillard
authors.affiliation: Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: C
authors.initials: C
authors.lastname: David James
authors.affiliation: Department of Neurological Surgery, Brain Tumor Center, University of California, San Francisco, CA, USA.|Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA.|Epidemiology and Biostatistics, University of California, San Francisco, CA, USA.
authors.forename: Annette M
authors.initials: AM
authors.lastname: Molinaro
authors.affiliation: Institute for Human Genetics, Department of Pediatrics, University of California, San Francisco, CA, USA.
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Shieh
authors.affiliation: Department of Neurological Surgery, Brain Tumor Center, University of California, San Francisco, CA, USA.|Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA.|Department of Pathology, Division of Neuropathology, University of California, San Francisco, CA, USA.
authors.forename: Joanna J
authors.initials: JJ
authors.lastname: Phillips
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000000981:diagnostic imaging* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism*; D005909:Glioblastoma / Q000000981:diagnostic imaging* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D018613:Microscopy, Confocal; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D017384:Sequence Deletion; D059008:Time-Lapse Imaging
chemical_list: C541485:EGFR protein, mouse; D066246:ErbB Receptors
keywords: RTK activity; extracellular matrix; invasion; tumor heterogeneity; vessel co-option