SMPD3-mediated extracellular vesicle biogenesis inhibits oligodendroglioma growth
Balakrishnan, A.; Adnani, L.; Chinchalongporn, V.; Vasan, L.; Prokopchuk, O.; Chen, M.; El-Sehemy, A.; Olender, T.; Touahri, Y.; Ahmad, S. T.; Islam, R.; Sujanthan, S.; Zinyk, D.; Comanita, L. C.; Kan, B.; Fleming, T.; Leong, H. S.; Morshead, C. M.; Brand, M.; Wallace, V. A.; Chan, J. A.; Schuurmans, C.
Show abstract
Isocitrate dehydrogenase (IDH) mutant gliomas, including oligodendroglioma (IDH-O) and astrocytoma (IDH-A), have signature slow-growth rates that are poorly understood. Here, we reveal that SMPD3, a ceramide-producing sphingomyelinase implicated as a tumor suppressor gene and involved in extracellular vesicle biogenesis, suppresses IDH-mutant tumor growth via autocrine and paracrine actions. In patients with IDH-mutant gliomas, higher SMPD3 expression levels correlate with longer survival, consistent with ceramide acting as an anti-oncometabolite. SMPD3 knock-down in patient-derived IDH-O cells enhances proliferation cell-autonomously in 2D-culture and 3D-human cerebral organoids, and accelerates tumor growth in mouse orthotopic xenografts. Supporting paracrine actions, IDH-O-derived extracellular vesicles, enriched in ribosomal proteins, induce astrocytic death in vitro. Furthermore, non-neoplastic glia in IDH-O tumors proliferate abnormally yet undergo apoptosis, concomitant with the acquisition of a translation-enriched transcriptional signature by tumor-associated oligodendrocytes. SMPD3 thus suppresses IDH-mutant glioma growth cell-autonomously and phenotypically alters normal glia via extracellular vesicle biogenesis and paracrine actions.
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