A Neuroimmune‐Oncology Microphysiological Analysis Platform (NEO‐MAP) for Evaluating Astrocytic Scar Formation and Microgliosis in Glioblastoma Microenvironment

This study presents a microfluidic-based NEuroimmune-Oncology Microphysiological Analysis Platform (NEO-MAP) platform reconstructing neuroimmune interactions in glioblastoma tumor microenvironment. The platform recapitulates physiological distribution of microglia and astrocytes, heterogeneous microglial phenotype, and astrocytic scar formation with chondroitin sulfate proteoglycans (CSPGs) extracellular matrix. The platform reveals enhanced astrocytic scar formation and a proinflammatory transformation of microglia associated with mTORC2-downregulated glioblastoma.

Abstract

Glioblastoma multiforme (GBM) is the most aggressive type of brain tumor, characterized by its heterogeneity in cellular components, including reactive astrocytes and microglia. Since neuroimmune responses like astrogliosis and microgliosis gain recognition as vital factors in brain tumor progression, there is a growing need for clinically relevant models that assess the interactions between astrocytes, microglia, and GBM. Here, a NEuroimmune-Oncology Microphysiological Analysis Platform (NEO-MAP) is presented as a “new map” to observe astrocytic scar formation and microgliosis in response to GBM. NEO-MAP based on pathophysiological principles is designed to replicate the GBM-glia interactions, multi-phenotypic microglia activities, scar-forming astrocytes with chondroitin sulfate proteoglycans (CSPGs) in the extracellular matrix, and the biophysical characteristics of the astrocytic scar barrier. The NEO-MAP reveals that inhibiting mTORC2 in GBM promotes the proinflammatory transformation of astrocytes and enhanced astrocytic scar formation. Astrocytes that form scars prompted microglia to change from the M2 to M1 phenotype, enhancing chemotherapy sensitivity. Tissues from GBM patients show a significant correlation between reduced mTORC2 activity and increased astrogliosis, alongside a decrease in M2-polarized microgliosis, aligning with the NEO-MAP findings. Overall, the NEO-MAP is foreseen as a clinically significant tool for exploring tumor-glia interactions, opening avenues for drug development aimed at the tumor microenvironment.