Glioblastoma multiforme cell communication is mediated by extracellular vesicles during temozolomide treatment

Glioblastoma multiforme (GBM) is the most common malignant primary brain tumour, and is characterised by high aggressiveness, heterogeneity, and resistance to therapy. Despite the combination of surgical resection of the tumour, radiotherapy, and chemotherapy with temozolomide (TMZ), the estimated median survival is only 15 months1. Recently, extracellular vesicles (EVs) have received increasing attention for their multiple roles in cell-cell communication. EVs are membrane-enclosed nanoscale vesicles that can modulate the behaviour of recipient cells by transporting biologically active molecules between cells2. In this study, we focused on EVs derived from TMZ-sensitive and TMZ-resistant GBM cell lines. We characterised GBM-derived EVs using electron microscopy, atomic force microscopy, and proteomic analysis, which revealed differences not only between EVs isolated from different GBM cell lines, but also between EVs isolated from TMZ-treated and untreated cells. Based on the proteomics data, we focused on a resistant (U251MG) and a sensitive (U87MG) cell line to study the effect of EVs treatment. Analysis of migration and cell death rates was performed after treating both GBM cell lines with EVs isolated from the same cell line and EVs isolated from the different cell line. In particular, the treatment of sensitive GBM cells with EVs isolated from resistant cells and vice versa showed that EVs do indeed transfer resistance or sensitivity information to TMZ to the recipient GBM cells. Interestingly, when EVs isolated from a sensitive cell line were incubated with resistant GBM cells, an increase in migration activity and cell death markers was observed. This research provides new insights into the variability of GBM-derived EVs and their multiple effects on recipient cells. References 1. Dapash M et al. Cells 2021;10(9):2257. 2. van Niel G et al. Nat Rev Mol Cell Biol 2018;19(4):213-228.