Investigating FGFR and FAK Signaling in Glioblastoma Stem Cells

• Matthew Shuhay, Biological Sciences, University of Delaware
• Marian Wehner, Biological Sciences, University of Delaware

• Deni Galileo, Biological Sciences, University of Delaware

Glioblastoma (GBM) is an aggressive and incurable form of brain cancer characterized by poor prognosis and rapid proliferation.  These tumors contain both “differentiated” GBM cells and Glioblastoma Stem Cells (GSC) that rapidly invade surrounding brain tissue.  GSCs make treatment difficult because they are resistant to radiation and chemotherapy and facilitate tumor recurrence.  Current GBM treatment includes surgical resection and radiation.  Prior work in our lab showed that exposing GSCs to sublethal doses of radiation can increase their proliferation but reduce their motility. Thus, radiation might contribute to tumor regrowth and therapeutic resistance, an idea that opposes current medical treatment of GBM.  Our work focuses on the role of Fibroblast Growth Factor Receptor (FGFR) and Focal Adhesion Kinase (FAK) cell signaling in GSCs and differentiated GBM cells. These two pathways are known to influence GBM cell proliferation and motility. Using human tumor derived GSCs, we are investigating differences in FGFR and FAK signaling in irradiated GSCs, nonirradiated GSCs, and differentiated GBM cell populations using western blotting and flow cytometry.  Differences in signaling will be correlated with cell proliferation rates and motility in vitro and with tumor-forming and invasive abilities in vivo in our chick embryo brain tumor model system.  For in vivo studies, fluorescently labeled GSCs, both irradiated and non-irradiated, are injected into E5 midbrain ventricles. Both cell types contribute to forming tumors.  In some mixed tumors, there was “sorting out,” where irradiated GSCs were located in the interior of the tumor, and non-irradiated GSCs were located superficially.  Although the potential differences in intracellular signaling have yet to be elucidated, our results suggest that radiation alters GSC behavior that likely involves differences in FGFR and FAK signaling. These differences could identify FGFR and FAK signaling as potential targets for treating initial and recurrent GBM.