title: Neutralizing the EGF receptor in glioblastoma cells stimulates cell migration by activating uPAR-initiated cell signaling.
abstract: In glioblastoma (GBM), the EGF receptor (EGFR) and Src family kinases (SFKs) contribute to an aggressive phenotype. EGFR may be targeted therapeutically; however, resistance to EGFR-targeting drugs such as Erlotinib and Gefitinib develops quickly. In many GBMs, a truncated form of the EGFR (EGFRvIII) is expressed. Although EGFRvIII is constitutively active and promotes cancer progression, its activity is attenuated compared with EGF-ligated wild-type EGFR, suggesting that EGFRvIII may function together with other signaling receptors in cancer cells to induce an aggressive phenotype. In this study, we demonstrate that in EGFRvIII-expressing GBM cells, the urokinase receptor (uPAR) functions as a major activator of SFKs, controlling phosphorylation of downstream targets, such as p130Cas and Tyr-845 in the EGFR in vitro and in vivo. When EGFRvIII expression in GBM cells was neutralized, either genetically or by treating the cells with Gefitinib, paradoxically, the cells demonstrated increased cell migration. The increase in cell migration was explained by a compensatory increase in expression of urokinase-type plasminogen activator, which activates uPAR-dependent cell signaling. GBM cells that were selected for their ability to grow in vivo in the absence of EGFRvIII also demonstrated increased cell migration, due to activation of the uPAR signaling system. The increase in GBM cell migration, induced by genetic or pharmacologic targeting of the EGFR, was blocked by Dasatinib, highlighting the central role of SFKs in uPAR-promoted cell migration. These results suggest that compensatory activation of uPAR-dependent cell signaling, in GBM cells treated with targeted therapeutics, may adversely affect the course of the disease by promoting cell migration, which may be associated with tumor progression.
authors.affiliation: Department of Pathology, University of California San Diego, La Jolla, CA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Hu
authors.affiliation: Department of Pathology, University of California San Diego, La Jolla, CA, USA.
authors.forename: K A
authors.initials: KA
authors.lastname: Muller
authors.affiliation: 1] Department of Pathology, University of California San Diego, La Jolla, CA, USA [2] The Ludwig Institute for Cancer Research, University of California San Diego, La Jolla, CA, USA.
authors.forename: F B
authors.initials: FB
authors.lastname: Furnari
authors.affiliation: 1] The Ludwig Institute for Cancer Research, University of California San Diego, La Jolla, CA, USA [2] Department of Medicine, University of California San Diego, La Jolla, CA, USA.
authors.forename: W K
authors.initials: WK
authors.lastname: Cavenee
authors.affiliation: Department of Pathology, University of California San Diego, La Jolla, CA, USA.
authors.forename: S R
authors.initials: SR
authors.lastname: VandenBerg
authors.affiliation: Department of Pathology, University of California San Diego, La Jolla, CA, USA.
authors.forename: S L
authors.initials: SL
authors.lastname: Gonias
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics / Q000473:pathology*; D002465:Cell Movement / Q000187:drug effects* / Q000235:genetics; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics; D000077156:Gefitinib; D005909:Glioblastoma / Q000235:genetics / Q000473:pathology*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010766:Phosphorylation / Q000187:drug effects; D011799:Quinazolines / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics; D055293:Receptors, Urokinase Plasminogen Activator / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D011799:Quinazolines; D034741:RNA, Small Interfering; D055293:Receptors, Urokinase Plasminogen Activator; C410723:epidermal growth factor receptor VIII; D066246:ErbB Receptors; D019061:src-Family Kinases; D000077156:Gefitinib