ABSTRACT

Glioblastoma (GBM) is the most common and aggressive brain tumor in adults with poor prognosis and rare long-term survival. Molecular classification revealed three distinct GBM subgroups and has helped to shine light on the tumor’s inter/intratumoral heterogeneity. Recent studies showed that these subgroups are flexible and differ spatially and temporally within patient tumors. Interestingly, plasticity between these subtypes in which the proneural (PN) glioma stem-like cells undergo transition into the more aggressive mesenchymal (MES) subtype has been observed. Extracellular vesicles (EVs) are considered a heterogeneous group of membrane-limited vesicles originating from the plasma membrane or endosome. They are secreted by nearly every cell and have been shown to play a key role in GBM progression by acting as multifunctional signaling complexes. We show that MES cells derived EVs modulate PN cells to increase proliferation, migration potential, stemness, invasiveness, aggressiveness, and therapeutic resistance by inducing mesenchymal transition through NF-KB/STAT3 signaling. Our findings could potentially help explore novel treatment strategies targeting intratumoral EV crosstalk and further suggest that EVs play a role in mesenchymal transition of other tumor types.