SMPD3 suppresses oligodendroglioma growth via dual autocrine-paracrine roles
10 affiliations
- 1Sunnybrook Research Institute
- 2Center of Excellence in Neuro-Oncology Sciences, St. Jude Children’s Research Hospital
- 3Department of Laboratory Medicine and Pathobiology, University of Toronto
- 4Ottawa Hospital Research Institute
- 5Department of Pathology and Laboratory Medicine, University of Calgary
- 6Department of Neurological Surgery, University of California San Francisco
- 7Institute of Medical Science, University of Toronto
- 8Donald K. Johnson Eye Institute, University Health Network Research Institute
- 9Donnelly Centre for Cellular and Biomolecular Research, University of Toronto
- 10Pittsburgh Heart, Lung, and Blood Vascular Medicine Institute, University of Pittsburgh School of Medicine
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.
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BibTeX
@article{saleh2026smpd3,
title = {{SMPD3 suppresses oligodendroglioma growth via dual autocrine-paracrine roles}},
author = {Fermisk Saleh and Anjali Balakrishnan and Lata Adnani and Shiekh Tanveer Ahmad and Vorapin Chinchalongporn and Ahmed El-Sehemy and Thomas Olender and Myra J. Chen and Aditya Kshirsagar and Andrew Kennedy and Nilakshi Kulathunga and Oleksandr Prokopchuk and Lakshmy Vasan and Yacine Touahri and Rehnuma Islam and Sajeevan Sujanthan and Dawn Zinyk and Lacrimioara C. Comanita and Boris Kan and Taylor Fleming and Iacovos P. Michael and Cindi M. Morshead and Hon S. Leong and Satoshi Okawa and Marjorie Brand and Valerie A. Wallace and Jennifer A. Chan and Carol Schuurmans},
journal = {Communications Biology},
year = {2026},
month = jun,
doi = {10.1038/s42003-026-10556-7},
url = {https://doi.org/10.1038/s42003-026-10556-7},
note = {CC BY},
}
RIS
TY - JOUR
TI - SMPD3 suppresses oligodendroglioma growth via dual autocrine-paracrine roles
AU - Fermisk Saleh
AU - Anjali Balakrishnan
AU - Lata Adnani
AU - Shiekh Tanveer Ahmad
AU - Vorapin Chinchalongporn
AU - Ahmed El-Sehemy
AU - Thomas Olender
AU - Myra J. Chen
AU - Aditya Kshirsagar
AU - Andrew Kennedy
AU - Nilakshi Kulathunga
AU - Oleksandr Prokopchuk
AU - Lakshmy Vasan
AU - Yacine Touahri
AU - Rehnuma Islam
AU - Sajeevan Sujanthan
AU - Dawn Zinyk
AU - Lacrimioara C. Comanita
AU - Boris Kan
AU - Taylor Fleming
AU - Iacovos P. Michael
AU - Cindi M. Morshead
AU - Hon S. Leong
AU - Satoshi Okawa
AU - Marjorie Brand
AU - Valerie A. Wallace
AU - Jennifer A. Chan
AU - Carol Schuurmans
PY - 2026
DA - 2026/06/01
JO - Communications Biology
DO - 10.1038/s42003-026-10556-7
UR - https://doi.org/10.1038/s42003-026-10556-7
AB - 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.
SN - 2399-3642
ER -