Characterization and Targeting of Glioblastoma Peritumoral Cells

Glioblastoma (GB) is a highly aggressive and resistant brain tumor with a dismal prognosis due to its extreme heterogeneity. Recurrences often occur near the resection cavity, suggesting their origin from the peritumoral cells. Here, we utilize GB’s invasion and migration capacity to lure and trap glioblastoma cells in the hydrogel, especially the infiltrative peritumoral cells, potentially offering a novel therapeutic approach. The study first identified prospective chemoattractants and potential cell cultures used for the development of CD44-targeting nanoparticles by analyzing the RNA microarray of GB cell cultures. Then, the migration ability of matched GB cell cultures derived from bulk and edge tissue towards four chemokines CXCL12, CCLL11, CXCL10, and OSM in a two-dimensional manner with transwell migration assay was investigated and was found to be specifically responsive to CXCL12 and CCL11. Then, the effect of these chemokines on the proliferation and functional properties of the cell cultures was tested with immunostaining, clonogenic assay, and collagen invasion assay. Next, we evaluated the glioblastoma cells’ migration through three-dimensional space with CXCL12-encapsulated hydrogel. Lastly, the safety of hyaluronan-based hydrogel was confirmed with mouse brain slice cultures, underscoring its potential to be used as a therapeutic method. Overall, this thesis illustrates the importance of studying cell migration and invasive behavior of GB, particularly peritumoral cells, and exploits this behavior to develop a hyaluronan-based hydrogel to attract and trap these infiltrative cells. By identifying key chemoattractants such as CXCL12 and CCL11 and validating their effects on cell migration and function as well as proof-of-concept of hydrogels in attracting GB cells, this research establishes a foundation for localized therapy.