TMIC-21. TARGETING INVADOPODIA TO BLOCK IONIZING RADIATION-INDUCED GLIOBLASTOMA CELL INVASION

Abstract

Abstract BACKGROUND Glioblastoma multiforme (GBM) is a highly heterogeneous and aggressive brain tumour that is considered incurable. The majority of GBM patients have a median survival of 15 months despite undergoing extensive treatment. The principal reason for poor outcome is a high rate of recurrence, often due to the tumours cells escaping therapy by infiltrating into the surrounding healthy brain tissue. Previous work from our lab suggests tumour cells that survive radiation therapy (RT) exhibit a more aggressively metastatic phenotype. We hypothesize that RT may increase GBM cell invasion by promoting the activity of invadopodia. Invadopodia are protrusions of the plasma membrane that secrete matrix metalloproteinases to degrade surrounding tissue. Further understanding of the mechanisms by which RT regulates invadopodial biology may lead to new therapeutic strategies to slow or halt the invasion of GBM cells and extend the lives of patients. RESULTS Three human GBM cell lines were exposed to 0, 2, or 5 Gy of ionizing radiation (IR) prior to quantification of cell viability by clonogenic survival assays. Invasion was investigated using a Transwell Matrigel Invasion Assay 48 hours post-IR. Exposure to 2 Gy IR increased invasion of LN229 and U87-MG cells but not LN18 cells. These data suggest that clinically relevant levels of radiation (2 Gy) increases the invasiveness of a subset of GBM cells in vitro. We are currently analyzing proteomic changes in LN229, U87-MG, and LN18 cells post-IR to identify novel drivers of IR-induced GBM cell invasion. Future work will involve genetically or pharmacologically inhibiting the proteins identified via mass spectrometry to determine their role in therapy induced invadopodia-mediated GBM cell invasion. SIGNIFICANCE: Recent evidence suggests tumour cells that survive RT exhibit a more aggressive phenotype. Identifying novel therapeutic targets to limit IR-induced GBM invasion may help to increasing the efficacy of current brain cancer therapy.