Extracellular vesicles as biomarkers in gliomas and their role in tumor progression

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Exosomes and microvesicles are extracellular vesicles (EVs) that are involved in the communication between different tumor cells and also between tumor cells and host cells. EVs contain RNA, DNA and protein, and the uptake of tumor cell-derived EVs (tEVs) can manipulate the phenotype of recipient cells. In glioblastomas, which represent the most frequent type of malignant brain tumors, tEVs contribute to oncogenic signaling, angiogenesis, immunosuppression and treatment resistance. tEVs are further released into the blood circulation, where molecules inside EVs are protected from degradation, rendering circulating EVs a potentially valuable biomarker source to monitor tumor evolution and treatment response. Our project pursues two major goals. First, we aim to perform an in-depth analysis of the molecular cargo contained in glioma EVs, in order to assess whether the complex mutational, epigenetic, transcriptional and proteomic profile of the original tumor is reflected in the tEVs. Our preliminary work revealed that the number of circulating EVs is elevated in the plasma of glioblastoma patients and we aim to trace both EV counts as well as tumor-specific genetic alterations in circulating EVs longitudinally in glioma patients, in order to determine whether EVs obtained by liquid biopsy allow dynamic monitoring of the tumor state and response to therapy. Second, we aim to map the dissemination of glioma-derived EVs throughout the body in immunocompetent and immunodeficient mouse models. Preliminary work from our group showed that purified glioma cell-derived EVs injected into the mouse brain parenchyma accumulate in deep cervical lymph nodes. We will investigate whether these EVs are transported through the meningeal lymphatic and glymphatic system and/or via hematogenous pathways and whether tEVs accumulate also in peripheral organs. Further, we will assess the effect of the immune system on EV dissemination and examine whether the uptake of glioma-derived EVs by microglia and macrophages reprograms these cells toward a more immunosuppressive phenotype in vivo. Collectively, these studies will show whether glioma EVs can be used as a biomarker source to obtain diagnostic information and examining disease progression and whether EVs are distributed through lymphatic pathways and contribute to tumor-induced immunosuppression in vivo.