HA Concentration-Dependent Invasion of Patient-Derived Gliomaspheres in 3D Hydrogels
Glioblastoma (GBM) is the most common and lethal primary central nervous system (CNS) tumor with a median survival of 12 – 15 months post-diagnosis. GBM aggression is, in part, due to high invasion of tumor cells into the CNS parenchyma which leads to therapeutic evasion as well as tumor recurrence. Mechanochemical cues within the GBM tumor microenvironment create environments conducive for cell survival and migration. Bioengineered in vitro systems which mimic features of the peritumoral niche can recapitulate in vivo GBM tumor cell behavior ex vivo. Thus, we developed three-dimensional (3D), hyaluronan (HA)-based hydrogels of varied HA concentrations and similar poroelastic properties corresponding to the peritumoral environment. Patient-derived spheroids encapsulated in our 3D hydrogels each displayed unique degrees and morphologies of invasion independent of conventional GBM molecular classification. We discovered strengths of cytoskeletal engagement, mediated by ezrin-radixin-moesin (ERM) complex, determined the propensity for cellular invasion, while cluster of differentiation 44 (CD44) expression densities determined the amounts of invasion. Furthermore, blocking the HA binding domain of receptor for hyaluronan-mediated motility (RHAMM) resulted in increased invasion, suggesting further studies on the roles of extracellular RHAMM are critical for further understanding how HA within the TME affects GBM cell invasion.