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Glioblastoma (GBM) is the most common malignant brain tumor and is characterized by its ability to invade into the surrounding microenvironment of the brain. The invasiveness of GBM makes this cancer extremely hard to treat, leading to a median patient survival of less than 16 months. Interactions between the tumor and surrounding tumor microenvironment (TME) play a key role in glioma invasion. Previous data from our xenograft mouse tumor implant model displays increased invasion in regions of fluid flow. Using this model, we identified an upregulation of sphingosine-1-phosphate receptor 3 (S1PR3) in the TME in regions of flow. We used a syngeneic GL261 mouse model and found S1PR3-/- mice display decreased flow-mediated glioma invasion in comparison to wild type mice. To further understand the individual contributions of the S1PR3-presenting cells in the TME, we have examined the role of S1PR3 in our in vitro system. This system is based on patient derived cellular ratios and incorporates collagen-hyaluronan hydrogels placed within 96 well tissue culture insert plates. The tunability of this model allows for interactions between various cell types and the impact of fluid flow on invasion to be examined. To examine the role of S1PR3 on invasion, TY52156 (an S1PR3 inhibitor) was applied to different cellular combinations including: G34 alone (a patient-specific cell line), +astrocytes, +microglia, +TME (astrocytes and microglia). A significant decrease in G34 flow stimulated invasion was observed with TY52156 but only in the presence of the TME or microglia alone. This data suggests that TY52156 thwarts the effects of flow and the microglia contributions to invasion. To further this work we plan to identify and evaluate other S1PR3-expressing cell types from mouse tumor implant samples using immunohistochemistry staining. This information will be used to determine further components that can be examined in our in vitro model.

TMIC-33. INVESTIGATING S1PR3-MEDIATED GLIOBLASTOMA INVASION MECHANISMS USING 3D HYDROGEL - TISSUE CULTURE INSERT MODEL