Matrix Stiffness Modulates Patient-Derived Glioblastoma Cell Fates in Three-Dimensional Hydrogels

Cancer progression is known to be accompanied by changes in tissue stiffness. Previous studies have primarily employed immortalized cell lines and 2D hydrogel substrates, which do not recapitulate the 3D tumor niche. How matrix stiffness affects patient-derived cancer cell fate in 3D remains unclear. In this study, we report a matrix metalloproteinase-degradable poly(ethylene-glycol)-based hydrogel platform with brain-mimicking biochemical cues and tunable stiffness (40-26,600 Pa) for 3D culture of patient-derived glioblastoma xenograft (PDTX GBM) cells. Our results demonstrate that decreasing hydrogel stiffness enhanced PDTX GBM cell proliferation, and hydrogels with stiffness 240 Pa and below supported robust PDTX GBM cell spreading in 3D. PDTX GBM cells encapsulated in hydrogels demonstrated higher drug resistance than 2D control, and increasing hydrogel stiffness further enhanced drug resistance. Such 3D hydrogel platforms may provide a valuable tool for mechanistic studies of the role of niche cues in modulating cancer progression for different cancer types. Impact statement Cancer progression has been demonstrated to be accompanied by changes in tissue stiffness; however, how matrix stiffness affects patient-derived glioblastoma xenograft glioblastoma (PDTX GBM) cells in 3D remains elusive. By employing a biomimetic hydrogel platform with brain-mimicking biochemical cues and tunable stiffness (40-26,600 Pa), we demonstrated the effect of varying hydrogel stiffness on PDTX GBM cell proliferation, spreading, and drug resistance in 3D, which cannot be recapitulated using 2D culture. Such 3D hydrogel platforms may provide a valuable tool for mechanistic studies or drug discovery and screening using patient-derived GBM cells.