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Glioblastoma (GBM) remains one of the most difficult to treat malignancies facing modern medicine. The strong migratory and invasive capacity of GBM cells allows for diffuse invasion into neighboring healthy brain which presents a significant hurdle for complete surgical resection of these tumors. Unsurprisingly, even after receiving maximal surgical resection, radiation and chemotherapy, the majority of GBM patients end up with recurrent disease. Increased expression levels of the homeostatic iron regulator gene (HFE) in brain tumors such as GBM have been associated with poorer outcomes. In order to better understand how HFE expression impacts the adhesive and migratory capacity of GBM, we utilized syngeneic mouse glioma models (KR158, CT2A) that have been transfected to either over-express or under-express HFE. We observed that knocking down HFE in the KR158 model resulted in significantly decreased migratory capacity as well as decreased adhesion to fibronectin and artificial basement membrane. Likewise, overexpressing HFE in a CT2A model resulted in increased adhesion to fibronectin or artificial basement membrane. Since HFE is known to regulate iron uptake, we studied how modulating the iron status of GBM cells impacted their ability to migrate and adhere. We found that increasing the iron pool of these mouse glioma models by exposure to exogenous iron compounds decreased migratory capacity. To better understand mechanistically how HFE and iron status impacted migration and adhesion, we probed how expression of integrins and their downstream signaling molecules, the Rho GTPases were altered in response to iron. We found that exposure to iron decreased levels of the Rho GTPases Cdc42 and RhoA. Furthermore, cells that overexpressed HFE were found to have increased expression of integrin β1 and integrin α5 suggesting that HFE and iron may impact integrins and their downstream signaling pathways to alter migration of GBM cells.

TAMI-42. THE ROLE OF HFE AND IRON IN CELL ADHESION AND MIGRATION IN GLIOBLASTOMA