SMPD3 -mediated extracellular vesicle biogenesis inhibits oligodendroglioma growth

Oligodendrogliomas are lower-grade, slow-growing gliomas that are ultimately fatal. Although driver mutations are known, the mechanisms underlying their signature slow growth rates are poorly understood. We found evidence for intra-tumoral interactions between neoplastic and non-neoplastic cells in oligodendroglioma tissues. To further study these cell interactions, we used two patient-derived oligodendroglioma cell lines of lower and higher aggressivity. Both oligodendroglioma cell lines released extracellular vesicles that had cytotoxic effects on non-neoplastic and neoplastic cells, but each had distinct vesicular proteomes. Consistent with extracellular vesicles mediating growth inhibitory effects in oligodendrogliomas, higher expression levels of several extracellular vesicle biogenesis genes ( correlates with longer survival in oligodendroglioma patients. Furthermore, overexpression slows oligodendroglioma cell growth in culture. Conversely, knockdown enhances oligodendroglioma proliferation , in murine xenografts, and in human cerebral organoid co-cultures. Oligodendroglioma-derived extracellular vesicles thus mediate tumor cell microenvironmental interactions that contribute to low aggressivity.