2. Academic Validation
  3. Endothelial cells-derived SEMA3G suppresses glioblastoma stem cells by inducing c-Myc degradation

Endothelial cells-derived SEMA3G suppresses glioblastoma stem cells by inducing c-Myc degradation

  • Cell Death Differ. 2025 Jun 18. doi: 10.1038/s41418-025-01534-3.
Peng-Xiang Min # 1 2,  Li-Li Feng # 3,  Yi-Xuan Zhang 3,  Chen-Chen Jiang 3,  Hong-Zhen Zhang 3,  Yan Chen 1,  Kohji Fukunaga 4,  Fang Liu 2,  Yu-Jie Zhang 1,  Takuya Sasaki 5,  Xu Qian 6,  Katsuhisa Horimoto 7 8,  Jian-Dong Jiang 9 10,  Ying-Mei Lu 11 12,  Feng Han 13 14 15
Affiliations

Affiliations

  • 1 Key Laboratory of Modern Toxicology of Ministry of Education; School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China.
  • 2 The Second People's Hospital of Changzhou, The Third Affiliated Hospital of Nanjing Medical University, Changzhou Medical Center, Nanjing Medical University, Changzhou, China.
  • 3 Medical Basic Research Innovation Center for Cardiovascular and Cerebrovascular Diseases, Ministry of Education; International Joint Laboratory for Drug Target of Critical Illnesses; Jiangsu Key Laboratory of Drug Targets and Translational Medicine for Cardio-cerebrovascular Diseases, School of Pharmacy, Nanjing Medical University, Nanjing, China.
  • 4 Department of CNS Drug Innovation, Graduate School of Pharmaceutical Sciences, Tohoku University, Miyagi, Japan.
  • 5 Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
  • 6 Department of Neurosurgery of First Affiliated Hospital of Nanjing Medical University, Department of Nutrition and Food Hygiene of School of Public Health, Nanjing Medical University, Nanjing, China.
  • 7 SOCIUM Inc. AIST Waterfront Center Annex 5 F, Aomi 2-4-7, Kotoku, Tokyo, Japan.
  • 8 Saitama Medical University International Medical Center, 1397-1 Yamane, Hidaka, Saitama, Japan.
  • 9 Medical Basic Research Innovation Center for Cardiovascular and Cerebrovascular Diseases, Ministry of Education; International Joint Laboratory for Drug Target of Critical Illnesses; Jiangsu Key Laboratory of Drug Targets and Translational Medicine for Cardio-cerebrovascular Diseases, School of Pharmacy, Nanjing Medical University, Nanjing, China. jiang.jdong@163.com.
  • 10 Department of Virology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. jiang.jdong@163.com.
  • 11 Key Laboratory of Modern Toxicology of Ministry of Education; School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China. lufx@njmu.edu.cn.
  • 12 Department of Nephrology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China. lufx@njmu.edu.cn.
  • 13 Medical Basic Research Innovation Center for Cardiovascular and Cerebrovascular Diseases, Ministry of Education; International Joint Laboratory for Drug Target of Critical Illnesses; Jiangsu Key Laboratory of Drug Targets and Translational Medicine for Cardio-cerebrovascular Diseases, School of Pharmacy, Nanjing Medical University, Nanjing, China. fenghan169@njmu.edu.cn.
  • 14 Institute of Brain Science, the Affiliated Brain Hospital of Nanjing Medical University, Nanjing, China. fenghan169@njmu.edu.cn.
  • 15 The affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Northern Jiangsu Institute of Clinical Medicine, Huaian, China. fenghan169@njmu.edu.cn.
  • # Contributed equally.
PMID: 40533501 DOI: 10.1038/s41418-025-01534-3
Abstract

The poor prognosis of glioblastoma (GBM) patients is attributed mainly to abundant neovascularization and presence of glioblastoma stem cells (GSCs). GSCs are preferentially localized to the perivascular niche to maintain stemness. However, the effect of abnormal communication between endothelial cells (ECs) and GSCs on GBM progression remains unknown. Here, we reveal that ECs-derived SEMA3G, which is aberrantly expressed in GBM patients, impairs GSCs by inducing c-Myc degradation. SEMA3G activates NRP2/PLXNA1 in a paracrine manner, subsequently inducing the inactivation of Cdc42 and dissociation of Cdc42 and WWP2 in GSCs. Once released, WWP2 interacts with c-Myc and mediates c-Myc degradation via ubiquitination. Genetic deletion of Sema3G in ECs accelerates GBM growth, whereas SEMA3G overexpression or recombinant SEMA3G protein prolongs the survival of GBM bearing mice. These findings illustrate that ECs play an intrinsic inhibitory role in GSCs stemness via the SMEA3G-c-Myc distal regulation paradigm. Targeting SEMA3G signaling may have promising therapeutic benefits for GBM patients.

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