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Glioblastoma Inhibition: Targeting Tumour-derived Extracellular-Vesicle Driven Cell-Recruitment

Periodic Report Summary 3 - GLITTER (Glioblastoma Inhibition: Targeting Tumour-derived Extracellular-Vesicle Driven Cell-Recruitment)

Glioblastomas (GBMs) are malignant brain tumours and among the most aggressive human cancers. GBMs patients have an extremely poor survival rate due to a complete absence of adequate therapies capable of efficiently targeting GBM cells inside the brain. Recently, we demonstrated that GBM cells release pro-tumoural extracellular vesicles (EVs) into the bloodstream, which emerged as important intermediates in communication with distant peripheral cells in the body. Of note, the distribution of GBM-derived EVs can now be monitored in vivo by employing a novel Cre/LoxP mouse reporter model. This sophisticated imaging model enables the visualisation of normal peripheral cells that have taken up circulating GBM-derived EVs and allows for subsequent tracking of the recruitment of these cells to the tumour. Recent studies have shown that GBM-derived EVs have the capability to manipulate non-neoplastic cells, exploiting them for tumour expansion. Moreover, we now have evidence that GBM-derived EV receptor pathways can be identified and blocked, possibly causing stagnation of GBM tumour growth by preventing recruitment of essential support cells. We have identified EV receptors using unbiased RNAi screening, followed by interference with pro-tumoural EV uptake, using small molecule drugs in our GBM in vivo models. Finally, circulating GBM-derived EVs and their RNA content are also efficiently captured and internalised by blood platelets (PLTs) that can act as efficient EV carriers. Hence, PLTs isolated from the blood of GBM patients can serve as non-invasive biomarkers and companion diagnostics platform (via the newly developed thromboSeq assay), and which can be extended to other cancer types.