Scholarlink

<p>Oligodendrogliomas (ODGs) are slow-growing tumors with poorly defined biology. Here, we identify <i>SMPD3</i>, encoding neutral sphingomyelinase 2 (nSMase2), as a negative regulator of ODG progression via extracellular vesicle (EV) biogenesis and autocrine-paracrine signaling. High <i>SMPD3</i> expression correlates with longer survival in ODG and low-grade glioma patients. <i>SMPD3</i> 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, <i>SMPD3</i>-mediated EV signaling and ribosomal stress converge to regulate ODG proliferation, establishing <i>SMPD3</i> as a key regulator and potential therapeutic target.</p><p></p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

SMPD3 suppresses oligodendroglioma growth via dual autocrine-paracrine roles

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年6月27日

查看全文
  • 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

摘要

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.