Abstract

Brain cancer is a devastating disease given its extreme invasiveness and intricate location. Glioblastoma multiforme (GBM) is one of the most common forms of brain cancer, andcancer progression is often correlated with significantly altered tissue stiffness. To elucidate the effect of matrix stiffness on GBM cell fates, previous research is largely limited to 2D studies using immortalized cell lines, which has limited physiological relevance. The objective of the study is to develop gradient hydrogels with brain-mimicking stiffness range as a 3Din vitroGBM model for screening of the effects of matrix stiffness on GBM. To increase the physiological relevance, patient-derived tumor xenograft (PDTX) GBM cells were used. Our gradient platform allows formation of cell-containing hydrogels with stiffness ranging from 40 Pa to 1300 Pa within a few minutes. By focusing on a brain-mimicking stiffness range, this gradient hydrogel platform is designed for investigating brain cancer. Increasing stiffness led to decreased GBMproliferation and less spreading, which is accompanied bydownregulation of matrix-metalloproteinases (MMPs). Using temozolomide(TMZ) as a model drug, we demonstrate that increasing stiffness led to higher drug resistance by PDTX GBM cells in 3D, suggesting matrix stiffness can directly modulate how GBM cells respond to drug treatment. While the current study focuses on stiffness gradient, the set upmay also be adapted for screening othercancer niche cues such as how biochemical ligand gradientmodulatesbrain cancer progression and drug responses using reduced materials and time. This article is protected by copyright. All rights reserved.

View details for DOI 10.1002/jbm.a.37093

View details for PubMedID 32862485