Abstract PO-053: Targeting focal adhesions to limit radiation-induced glioblastoma cell invasion

Abstract

Abstract Introduction: Glioblastoma multiforme (GBM) is a grade IV brain tumor that is considered incurable with a median overall survival of 15 months. This low survival rate is partially attributed to the highly infiltrative nature of GBM cells. A key component of GBM cell invasion is the degradation of extracellular matrix (ECM), which is facilitated by the formation of invadosomes: focal adhesions (FAs) and invadopodia. The majority of GBM patients will receive a conventional radiation schedule of 2 Gy in 30 fractions, while a subset of patients will receive a hypofractioned radiation schedule of ~3 Gy in 15 fractions. Recent pre-clinical reports indicate the population of GBM cells that survive ionizing radiation (IR) exhibit increased invasiveness, suggesting IR may regulate FA and invadopodia function. Understanding how IR affects invadosome biology may lead to new therapeutic strategies to halt the invasion of GBM cells and increase overall survival of patients treated with radiation. Results: We found that irradiated GBM cells were significantly more invasive in vitro. GBM cells irradiated with 0-4 Gy and plated onto fluorescently-tagged gelatin to analyze ECM degradation. Cells exposed to 0-2 Gy IR produced small dot-like patterns of degradation resembling active invadopodia. However, cells exposed to 3-4 Gy IR produced oblong-shaped patterns of degradation at the periphery of the cell resembling active FAs. Using immunofluorescent markers of invadopodia (TKS5/actin) and FAs (vinculin), we found total focal adhesion and invadopodia formation remained unchanged. Rather, we found that exposing cells to 3 Gy IR increased pFAK-397 in FA structures suggesting IR increases ECM degradation by promoting FA activity. Conclusions: These data suggest higher IR doses promote FA-mediated ECM degradation and GBM cell invasion. We are currently investigating the impact of IR on FAs, ECM degradation, and GBM cell invasion in murine brain slices ex vivo. Citation Format: Lisa R. Decotret, Rocky Shi, Kevin L. Bennewith. Targeting focal adhesions to limit radiation-induced glioblastoma cell invasion [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr PO-053.