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SMPD3 suppresses oligodendroglioma growth via dual autocrine-paracrine roles
Fermisk Saleh1,2, Anjali Balakrishnan1,2, Lata Adnani1,3,4,5
1Sunnybrook Research Institute, Toronto, ON, Canada.
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.
Insights
Sphingomyelinase (SMPD3) regulates oligodendroglioma (ODG) growth by controlling extracellular vesicle (EV) signaling. Inhibiting SMPD3 or EV production accelerates tumor progression, highlighting SMPD3 as a therapeutic target.
Area of Science:
- Neuro-oncology
- Cancer Biology
- Molecular Medicine
Background:
- Oligodendrogliomas (ODGs) are slow-growing brain tumors with complex biology.
- The precise mechanisms regulating ODG progression remain poorly understood.
Purpose of the Study:
- To identify novel regulators of oligodendroglioma (ODG) progression.
- To investigate the role of SMPD3 and extracellular vesicle (EV) signaling in ODG growth.
Main Methods:
- Investigated SMPD3 expression in patient tumors and cell lines.
- Utilized cell culture, organoid invasion assays, xenografts, and chick CAM models.
- Assessed the impact of SMPD3 knockdown and pharmacological inhibitors on ODG proliferation and EV production.
Main Results:
- High SMPD3 expression correlates with improved survival in glioma patients.
- SMPD3 knockdown increased ODG proliferation, invasion, and tumor growth.
- ODG-derived EVs, enriched in ribosomal proteins, suppressed astrocyte proliferation.
- Inhibiting nSMase2 or ribosome biogenesis increased ODG proliferation.
Conclusions:
- SMPD3 acts as a negative regulator of ODG progression through EV biogenesis and signaling.
- A convergence of SMPD3-mediated EV signaling and ribosomal stress regulates ODG proliferation.
- SMPD3 represents a potential therapeutic target for oligodendrogliomas.
