GBM-derived Exosomes Containing GLUT3 Increase the Migratory Potential of Monocytes

Glioblastoma (GBM) remains a challenging malignancy with dismal prognoses despite aggressive treatment regimens. Intratumoral heterogeneity contributes to therapeutic resistance, with roles for stem cell-like brain tumor initiating cells (GBMs), glioma associated macrophages (GAMs), and communication between them. GAMs are derived from infiltrating lymphocytes, and monocyte migration is increased by GBM cell release of extracellular vesicles, including exosomes. GBM survival is promoted by the glucose transporter GLUT3, which was recently shown to alter macrophage activation states. We found that GBM-derived exosomes contain GLUT3 and that exosomes from GLUT3 expressing GBMs significantly increased monocyte migration in comparison to controls. Monocytes transfected with GLUT3 (but not GLUT1) also had significantly increased migration, demonstrating a direct role for GLUT3 in monocytes migration. Analysis of the transcriptome of exosome treated monocytes demonstrated that exosomes derived from GLUT3 expressing GBMs increasedGDF-15in monocytes. GDF-15 is a known regulator of monocyte migration, and we determined that knockdown of GDF-15 blocked the migration induced by GBM-derived exosomes. As GDF-15 induced monocyte migration is thought to involve MMP12, we next evaluated MMP12 as a potential mediator of the pro-migratory phenotype.MMP12was significantly increased in monocytes upon treatment with exosomes derived from GLUT3 expressing GBMs as was MMP12 activity. Together, our findings suggest a novel mechanism by which GBMs facilitate immune evasion and tumor progression: GBM-derived exosomes transfer GLUT3 to monocytes to increase a GDF-15/MMP12 pathway that promotes monocyte migration. The data also highlight the importance of understanding and targeting cell-cell interactions to improve glioblastoma treatment.