A patient-designed tissue-engineered model of the infiltrative glioblastoma microenvironment
R. Chase Cornelison, Jiaguo Yuan, Kinsley M. Tate, A. Petrosky, Garrett F. Beeghly, Mathew Bloomfield, Samantha C. Schwager, Alexandra L. Berr, Caleb A. Stine, Daniela Cimini, Fahad Bafakih, James W. Mandell, Benjamin Purow, Bethany J. Horton, Jennifer M. Munson
Abstract
Abstract Glioblastoma is an aggressive brain cancer characterized by diffuse infiltration. Infiltrated glioma cells persist in the brain post-resection where they interact with glial cells and experience interstitial fluid flow. We use patient-derived glioma stem cells and human glial cells (i.e., astrocytes and microglia) to create a four-component 3D model of this environment informed by resected patient tumors. We examine metrics for invasion, proliferation, and putative stemness in the context of glial cells, fluid forces, and chemotherapies. While the responses are heterogeneous across seven patient-derived lines, interstitial flow significantly increases glioma cell proliferation and stemness while glial cells affect invasion and stemness, potentially related to CCL2 expression and differential activation. In a screen of six drugs, we find in vitro expression of putative stemness marker CD71, but not viability at drug IC 50 , to predict murine xenograft survival. We posit this patient-informed, infiltrative tumor model as a novel advance toward precision medicine in glioblastoma treatment.