Glioblastoma (GBM) is the most common and aggressive form of primary brain tumor with median survival of 12 months. To improve clinical outcomes， it is critical to develop in vitro models that support GBM proliferation and invasion for deciphering tumor progression and screening drug candidates. A key hallmark of GBM cells is their extreme invasiveness， a process mediated by matrix metalloproteinase (MMP)-mediated degradation of the extracellular matrix. We recently reported the development of a MMP-degradable， poly(ethylene-glycol)-based hydrogel platform for culturing GBM cells. In the present study， we modulated the percentage of MMP-degradable crosslinks in 3D hydrogels to analyze the effects of MMP-degradability on GBM fates. Using an immortalized GBM cell line (U87) as a model cell type， our results showed that MMP-degradability was not required for supporting GBM proliferation. All hydrogel formulations supported robust GBM proliferation， up to 10 fold after 14 days. However， MMP-degradability was essential for facilitating tumor spreading， and 50% MMP-degradable hydrogels were sufficient to enable both robust tumor cell proliferation and spreading in 3D. The findings of this study highlight the importance of modulating MMP-degradability in engineering 3D in vitro brain cancer models and may be applied for engineering in vitro models for other cancer types. © 2016 Wiley Periodicals， Inc. J Biomed Mater Res Part A: 105A: 770-778， 2017.