Year: 2026
Type: article
Abstract: Oligodendrogliomas (ODGs) are slow-growing tumors with poorly defined biology. Here, we identify SMPD3, encoding neutral sphingomyelinase 2 (nSMase2), as a negative regulator of ODG progression via extracellular vesicle (EV) biogenesis and autocrine-paracrine signaling. High SMPD3 expression correlates with longer survival in ODG and low-grade glioma patients. SMPD3 knockdown in patient-derived BT54 and BT88 cells increases proliferation, enhances BT88 invasion in cerebral organoids, and accelerates BT88-tumor growth in mouse xenografts and chick CAM assays. Patient tumors display abnormal non-neoplastic glial proliferation and a ribosome-rich transcriptional signature in tumor-associated oligodendrocytes. Concordantly, ODG-derived EVs, enriched in ribosomal proteins, suppress astrocyte proliferation. Pharmacological inhibition of nSMase2 (GW4869) or ribosome biogenesis (Rbin1, diazaborine) increases ODG cell proliferation while reducing protein synthesis. Blocking EV synthesis amplifies ribosome inhibition effects, whereas exogenous EVs attenuate them. Thus, SMPD3-mediated EV signaling and ribosomal stress converge to regulate ODG proliferation, establishing SMPD3 as a key regulator and potential therapeutic target.
Source: Communications Biology
Authors: Fermisk Saleh, Anjali Balakrishnan, Lata Adnani, Shiekh Tanveer Ahmad, Vorapin Chinchalongporn, Ahmed El-Sehemy, Thomas Olender, Myra J. Chen, Aditya Kshirsagar, Andrew Kennedy, Nilakshi Kulathunga, Oleksandr Prokopchuk, Lakshmy Vasan, Yacine Touahri, Rehnuma Islam, Sajeevan Sujanthan, Dawn Zinyk, Lacrimioara C. Comanita, Boris Kan, Taylor Fleming, Iacovos P. Michael, Cindi M. Morshead, Hon S. Leong, Satoshi Okawa, Marjorie Brand, Valerie A. Wallace, Jennifer A. Chan, Carol Schuurmans
Institutions: University of Toronto, Sunnybrook Hospital, Sunnybrook Research Institute, University of Calgary, Alberta Children's Hospital Research Institute, Hotchkiss Brain Institute, St. Jude Children's Research Hospital, University Health Network, Donald K. Johnson Eye Institute, Ottawa Hospital Research Institute, University of California, San Francisco, University of Pittsburgh, McGowan Institute for Regenerative Medicine, University of Wisconsin–Madison, University of Wisconsin Carbone Cancer Center
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $4,190
OpenAlex ID: W7166350145
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