Acquired temozolomide resistance instructs patterns of glioblastoma behavior in gelatin hydrogels

Acquired drug resistance in glioblastoma (GBM) presents a major clinical challenge and is a key factor contributing to abysmal prognosis, with less than 15 months median overall survival. Aggressive chemotherapy with the frontline therapeutic, temozolomide (TMZ), ultimately fails to kill residual highly invasive tumor cells after surgical resection and radiotherapy. Here, we report a three-dimensional (3D) engineered model of acquired TMZ resistance using two isogenically-matched sets of GBM cell lines encapsulated in gelatin methacrylol hydrogels. We benchmark response of TMZ-resistant vs. TMZ-sensitive GBM cell lines within the gelatin-based extracellular matrix platform and further validate drug response at physiologically relevant TMZ concentrations. We show changes in drug sensitivity, cell invasion, and matrix-remodeling cytokine production as the result of acquired TMZ resistance. This platform lays the foundation for future investigations targeting key elements of the GBM tumor microenvironment to combat GBMs devastating impact by advancing our understanding of GBM progression and treatment response to guide the development of novel treatment strategies. TeaserA hydrogel model to investigate the impact of acquired drug resistance on functional response in glioblastoma.