Matrix Stiffness Regulates GBM Migration and Chemoradiotherapy Responses via Chromatin Condensation in 3D Viscoelastic Matrices

Glioblastoma multiforme (GBM) progression is associated with changes in matrix stiffness, and different regions of the tumor niche exhibit distinct stiffnesses. Using elastic hydrogels, previous work has demonstrated that matrix stiffness modulates GBM behavior and drug responses. However, brain tissue is viscoelastic, and how stiffness impacts the GBM invasive phenotype and response to therapy within a viscoelastic niche remains largely unclear. Here, we report a three-dimensional (3D) viscoelastic GBM hydrogel system that models the stiffness heterogeneity present within the tumor niche. We find that GBM cells exhibit enhanced migratory ability, proliferation, and resistance to radiation in soft matrices, mimicking the tumor core and perifocal margins. Conversely, GBM cells remain confined and demonstrate increased resistance to chemotherapy in stiff matrices mimicking edematous tumor regions. We identify that stiffness-induced changes in the GBM phenotype are regulated by nuclear mechanosensing and chromatin condensation. Pharmacologically decondensing the chromatin significantly impedes GBM migration and overcomes stiffness-induced chemoresistance and radioresistance. Our findings highlight that stiffness regulates aggressive GBM behavior in viscoelastic matrices through mechanotransduction processes. Finally, we reveal the critical role of chromatin condensation in mediating GBM migration and therapy resistance, offering a potential new therapeutic target to improve GBM treatment outcomes.