Endothelial cells-derived SEMA3G suppresses glioblastoma stem cells by inducing c-Myc degradation
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.
Authors
- Pengxiang Min (ORCID: https://orcid.org/0000-0003-2228-7252)
- Jian‐Dong Jiang (ORCID: https://orcid.org/0000-0003-1173-685X)
- Katsuhisa Horimoto (ORCID: https://orcid.org/0000-0002-8328-6694)
- Kohji Fukunaga
- Ying‐Mei Lu (ORCID: https://orcid.org/0000-0003-3187-4344)
- Xu Qian (ORCID: https://orcid.org/0000-0003-1533-8568)
- Yixuan Zhang (ORCID: https://orcid.org/0000-0001-9781-6281)
- Yujie Zhang
- Fang Liu (ORCID: https://orcid.org/0000-0001-8140-6800)
- Yan Chen (ORCID: https://orcid.org/0009-0004-6856-263X)
- Chenchen Jiang (ORCID: https://orcid.org/0000-0002-6118-9594)
- Takuya Sasaki (ORCID: https://orcid.org/0000-0002-8091-8625)
- Feng Han (ORCID: https://orcid.org/0000-0002-4868-3491)
- Hongzhen Zhang (ORCID: https://orcid.org/0000-0003-4729-1928)
- Li-Li Feng
Institutions
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Tohoku University (JP)
- Huaian First People’s Hospital (CN)
- Satou Hospital (JP)
- Nanjing Brain Hospital (CN)
- Ministry of Education (KR)
- Changzhou No.2 People's Hospital (CN)
- Ministry of Education and Child Care (CA)
- Nanjing Medical University (CN)
- Tohoku Medical and Pharmaceutical University (JP)
- Saitama Medical University (JP)
Publication Details
- Journal
- Cell Death and Differentiation
- Published
- 2025-06-18
- DOI
- https://doi.org/10.1038/s41418-025-01534-3
- Citations
- 3
- Primary Topic
- Axon Guidance and Neuronal Signaling
- Type
- article
- Field-Weighted Citation Impact
- 2.73
Funders
- Nanjing Medical University
- National Key Research and Development Program of China