Journal article
Stress-induced pro-inflammatory glioblastoma stem cells secrete TNFAIP6 to enhance tumor growth and induce suppressive macrophages
Developmental cell, Vol.60(19), pp.2558-2575.e6
10/2025
DOI: 10.1016/j.devcel.2025.04.027
PMID: 40403724
Abstract
Glioblastoma (GBM) is the most aggressive primary intracranial tumor, with glioblastoma stem cells (GSCs) enforcing the intratumoral hierarchy. The inflammatory microenvironment influences tumor development at varying stages, while the underlying mechanism of GSCs facing pro-inflammatory stress remains unclear. Here, we show that, in human GBM, pro-inflammatory stress from pro-inflammatory macrophages (pTAMs) maintains GSC proliferation and self-renewal. Tumor necrosis factor alpha-induced protein 6 (TNFAIP6), as a responder in patient-derived GSCs to pro-inflammatory stress tumor necrosis factor alpha (TNF-α) from human pTAMs, promotes tumor growth through binding epidermal growth factor (EGF) and prolonging EGF receptor (EGFR)-phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT) signaling activation. Meanwhile, pro-inflammatory stress-induced patient-derived GSCs secrete TNFAIP6 to transform macrophage phenotype from pTAMs to inflammatory-suppressive macrophages (sTAMs). Collectively, pharmacological or genetic disruption of TNFAIP6 autocrine and paracrine communication between patient-derived GSCs and TAMs inhibited GSC proliferation and self-renewal in vitro and in patient-derived xenograft tumor-bearing mice, suggesting that TNFAIP6 is an effective target for GBM therapy.
Details
- Title: Subtitle
- Stress-induced pro-inflammatory glioblastoma stem cells secrete TNFAIP6 to enhance tumor growth and induce suppressive macrophages
- Creators
- Danling Gu - Nanjing Medical UniversityLang Hu - Nanjing Medical UniversityKailin Yang - Cleveland ClinicWei Yuan - Yancheng First People's HospitalDanyang Shan - Nanjing Medical UniversityJiancheng Gao - Nanjing Medical UniversityJiahuang Li - China Pharmaceutical UniversityRyan C Gimple - Washington University in St. LouisDeobrat Dixit - UPMC Hillman Cancer CenterZhe Zhu - Columbia University Irving Medical CenterDaqi Li - Nanjing Medical UniversityQiulian Wu - University of Pittsburgh Medical CenterZhumei Shi - Nanjing Medical UniversityYingyi Wang - Nanjing Medical UniversityNingwei Zhao - China Exposomics Institute, 781 Cai Lun Road, Shanghai 200120, ChinaKun Yang - Zhongda Hospital Southeast UniversityJunfei Shao - Wuxi People's HospitalFan Lin - Nanjing Medical UniversityQianghu Wang - Nanjing Medical UniversityGuangfu Jin - Nanjing Medical UniversityYun Chen - Nanjing Medical UniversityXu Qian - Nanjing Medical UniversityZhibin Hu - Nanjing Medical UniversityChaojun Li - Nanjing Medical UniversityNu Zhang - Sun Yat-sen UniversityYongping You - Jiangsu Province HospitalJian Liu - Nanjing University of Chinese MedicineQian Zhang - Nanjing Medical UniversityJunxia Zhang - Nanjing Medical UniversityJeremy N Rich - University of Pittsburgh Medical CenterXiuxing Wang - Wuxi People's Hospital
- Resource Type
- Journal article
- Publication Details
- Developmental cell, Vol.60(19), pp.2558-2575.e6
- DOI
- 10.1016/j.devcel.2025.04.027
- PMID
- 40403724
- NLM abbreviation
- Dev Cell
- ISSN
- 1878-1551
- eISSN
- 1878-1551
- Publisher
- CELL PRESS
- Grant note
- National Natural Science Foundation of China: 82072779, 82403427 Jiangsu Provincial Key Research Development Pro-gram of China: BE2022770 China Postdoctoral Science Foundation: 2023M741795 Computational Genomic Epidemiology of Cancer (CoGEC) Program at Case Comprehensive Cancer Center: T32CA094186 ASCO Conquer Cancer FoundationRSNA Research Fellow GrantResearch Personnel Cultivation Programme of Zhongda Hospital, Southeast University: CZXM-GSP-RC-152 Zhongda Hospital Affiliated to Southeast UniversityJiangsu Province High-Level Hospital Pairing Assistance Construction Funds: zdlyg05 Medical Science and Technology Development Foundation of Nanjing: ZKX22041
We thank the Nanjing Medical University Analysis Center for help with fluores-cence-activated cell sorting (FACS) and the animal core facility of Nanjing Medical University for help with animal experiments. This work was supported by the National Natural Science Foundation of China (82072779 to X.W. and 82403427 to D.G.) , the Jiangsu Provincial Key Research Development Pro-gram of China (BE2022770 to Y.C.) , and the China Postdoctoral Science Foundation (2023M741795 to D.G.) . Kailin Yang was supported by the Computational Genomic Epidemiology of Cancer (CoGEC) Program at Case Comprehensive Cancer Center (T32CA094186) , the Young Investigator Award in Glioblastoma from the ASCO Conquer Cancer Foundation, and the RSNA Research Fellow Grant. Kun Yang was supported by the Research Personnel Cultivation Programme of Zhongda Hospital, Southeast University (CZXM-GSP-RC-152) , Zhongda Hospital Affiliated to Southeast University, the Jiangsu Province High-Level Hospital Pairing Assistance Construction Funds (zdlyg05) , and the Medical Science and Technology Development Foundation of Nanjing (ZKX22041) .
- Language
- English
- Electronic publication date
- 05/15/2025
- Date published
- 10/2025
- Academic Unit
- Radiation Oncology
- Record Identifier
- 9984824302102771
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