SMPD3 suppresses oligodendroglioma growth via dual autocrine-paracrine roles
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.
Authors
- Yacine Touahri
- Myra J. Chen (ORCID: https://orcid.org/0000-0001-8633-1414)
- Marjorie Brand (ORCID: https://orcid.org/0000-0001-8915-8012)
- Iacovos P. Michael (ORCID: https://orcid.org/0000-0001-7674-1233)
- Lata Adnani (ORCID: https://orcid.org/0000-0002-2852-6915)
- Anjali Balakrishnan (ORCID: https://orcid.org/0000-0003-4010-6515)
- Valerie A. Wallace (ORCID: https://orcid.org/0000-0003-3721-9017)
- Vorapin Chinchalongporn
- Sajeevan Sujanthan (ORCID: https://orcid.org/0000-0002-3128-3977)
- Thomas Olender (ORCID: https://orcid.org/0000-0003-3617-5163)
- Shiekh Tanveer Ahmad (ORCID: https://orcid.org/0000-0002-9882-8636)
- Fermisk Saleh (ORCID: https://orcid.org/0000-0002-1585-8830)
- Aditya Kshirsagar (ORCID: https://orcid.org/0000-0001-8926-9353)
- Taylor Fleming (ORCID: https://orcid.org/0000-0002-2432-8102)
- Oleksandr Prokopchuk
- Rehnuma Islam (ORCID: https://orcid.org/0000-0002-8105-4486)
- Jennifer A. Chan (ORCID: https://orcid.org/0000-0001-9798-1551)
- Carol Schuurmans (ORCID: https://orcid.org/0000-0003-3567-0058)
- Cindi M. Morshead (ORCID: https://orcid.org/0000-0003-4605-4883)
- Lakshmy Vasan (ORCID: https://orcid.org/0000-0003-1153-7762)
- Nilakshi Kulathunga
- Satoshi Okawa
- Andrew Kennedy
- Dawn Zinyk
- Hon S. Leong
- Boris Kan
- Ahmed El-Sehemy
- Lacrimioara C. Comanita
Institutions
- St. Jude Children's Research Hospital (US)
- Sunnybrook Health Science Centre (CA)
- University of Calgary (CA)
- University of Pittsburgh (US)
- University of California, San Francisco (US)
- University of Toronto (CA)
- Toronto Rehabilitation Institute (CA)
- Ottawa Hospital (CA)
- Alberta Children's Hospital (CA)
- University of Wisconsin Carbone Cancer Center (US)
- Versiti Blood Center of Wisconsin (US)
- McGowan Institute for Regenerative Medicine (US)
- Neurological Surgery (US)
- Sunnybrook Hospital (CA)
- Ottawa Hospital Research Institute (CA)
- Sunnybrook Research Institute
- Hotchkiss Brain Institute (CA)
Publication Details
- Journal
- Communications Biology
- Published
- 2026-06-27
- DOI
- https://doi.org/10.1038/s42003-026-10556-7
- Primary Topic
- Glioma Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Cancer Research Society
- Sunnybrook Research Institute
- International Development Research Centre
- University of Toronto
- Terry Fox Research Institute
- Hospital for Sick Children
- Canada First Research Excellence Fund
- Scheme for Promotion of Academic and Research Collaboration