Extracellular vesicle pathways as regulators of tumor-vascular interactions in glioblastoma

Glioblastoma (GBM), the most prevalent astrocytic brain tumour, remains incurable in spite of decades of research. Florid neovascularization, a morphological hallmark of GBM, is still poorly understood, as is the role of blood vessels in mediating the access of immune cells into the tumour parenchyma. Studies on the interface between tumour-driving glioma stem cells (GSCs) and the vascular compartment in GBM led us to uncover new intercellular communication mechanisms mediated by extracellular vesicles (EVs) with major implications for blood vessel modulating therapies.

Thus, we observed that molecular profiles of GSC define their repertoire of EVs, which also changes as a function of induced GSC differentiation into astrocytic lineage. Notably, proneural subtype of GSCs forms brain tumours associated with mostly small angiogenic blood vessels, in conjunction with ample secretion of vascular endothelial growth factor (VEGF). In contrast, mesenchymal GSCs release blood vessel stimulating activities in both soluble and particulate fractions of the cellular secretome. The latter include the release EVs that carry oncogenic epidermal growth factor receptor (EGFRvIII), which is readily transferred to endothelial cells, whereupon it triggers a unique non-angiogenic blood vessel formation process, which we termed vasectasia. Vasectasia entails a VEGF-independent, circumferential vessel enlargement, resistant to angiogenesis inhibitors and linked to changes in endothelial cell subpopulation landscapes.

Conversely, we observed that endothelial cell-derived EVs impact the phenotype of tumour initiating GSCs. Interestingly, such EVs carry proteases that evoke angiocrine responses leading proneural GSC to adopt a more invasive, mesenchymal phenotype, coupled with reduced responsiveness to temozolomide (TMZ) chemotherapy. Finally, we report that the efficacy of TMZ treatment in mouse models of mesenchymal GBMcan be increased by induced alterations in vascular structures coupled with adoptive immunotherapy.

Thus, vesiculation mechanisms associated with glioblastoma represent an important and targetable mechanisms shaping tumour microenvironment and can be exploited for liquid biopsy approaches in adult and pediatric brain tumours.

Janusz Rak, MD, PhD is a Professor of Pediatrics and Jack Cole Chair in Pediatric Hematology/Oncology at McGill University. His laboratory investigates how oncogenic events drive cancer progression through orchestrating pathological intercellular communication networks, trigger vascular alterations and systemic vascular paraneoplastic syndromes. These studies currently focus on mechanisms mediated by extracellular vesicles (EVs; including exosomes) and their molecular content. He currently directs the CFI funded Centre for Applied Nanomedicine (CAN) and the NET program sponsored by Fondation Charles Bruneau and CIBC to investigate EV-based liquid biopsy approaches in pediatric cancer. He is a Fellow of the Royal Society of Canada.