Bioengineered scaffolds for 3D culture demonstrate extracellular matrix-mediated mechanisms of chemotherapy resistance in glioblastoma.

Bioengineered scaffolds for 3D culture demonstrate extracellular matrix-mediated mechanisms of chemotherapy resistance in glioblastoma. Matrix Biol. 2019 Apr 24;: Authors: Xiao W, Wang S, Zhang R, Sohrabi A, Yu Q, Liu S, Ehsanipour A, Liang J, Bierman RD, Nathanson DA, Seidlits SK Abstract Originating in the brain, glioblastoma (GBM) is a highly lethal and virtually incurable cancer, in large part because it readily develops resistance to treatments. While numerous studies have investigated mechanisms enabling GBM cells to evade chemotherapy-induced apoptosis, few have addressed how their surrounding extracellular matrix (ECM) acts to promote their survival. Here, we employed a biomaterial-based, 3D culture platform to investigate systematically how interactions between patient-derived GBM cells and the brain ECM promote resistance to alkylating chemotherapies - including temozolomide, which is used routinely in clinical practice. Scaffolds for 3D culture were fabricated from hyaluronic acid (HA) - a major structural and bioactive component of the brain ECM - and functionalized with the RGD (arginine-glycine-aspartic acid) tripeptide to provide sites for integrin engagement. Data demonstrate that cooperative engagement of CD44, through HA, and integrin αV, through RGD, facilitates resistance to alkylating chemotherapies through co-activation of Src, which inhibited downstream expression of BCL-2 family pro-apoptotic factors. In sum,...
Source: Matrix Biology - Category: Molecular Biology Authors: Tags: Matrix Biol Source Type: research