Low level of tumor necrosis factor α in tumor microenvironment maintains self-renewal of glioma stem cells by Vasorin-mediated glycolysis

  • Neuro Oncol. 2024 Aug 2:noae147. doi: 10.1093/neuonc/noae147.
Yang Zhang  1 ,  Tianxu Kang  2 ,  Yuxi Wang  2 ,  Chao Song  1 ,  Huan Li  1 ,  Hailong Mi  1 ,  Yachao Li  1 ,  Minhai Dong  3 ,  Xiaoyu Ma  3 ,  Hongtao Zhu  3 ,  Lidong Cheng  3 ,  Po Zhang  4 ,  Zhiye Chen  3 ,  Lin Zhou  1 ,  Qiulian Wu  4 ,  Feng Mao  3 ,  Baofeng Wang  3 ,  Suojun Zhang  3 ,  Kai Shu  3 ,  Feng Wan  5 ,  Wenchao Zhou  6 ,  Jeremy N Rich  4  7 ,  Jianying Shen  1 ,  Qungen Xiao  3 ,  Xingjiang Yu  1  8
Affiliations
  • 1. Department of Histology and Embryology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
  • 2. School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
  • 3. Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
  • 4. UPMC Hillman Cancer Center, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
  • 5. Department of Neurosurgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, 510080, China.
  • 6. Intelligent Pathology Institute, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230031, China.
  • 7. Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
  • 8. Hubei Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation.
PMID: 39093693 DOI: 10.1093/neuonc/noae147
Abstract

Background: Self-renewal of glioma stem cells (GSCs) is responsible for glioblastoma (GBM) therapy-resistant and recurrence. Tumor necrosis factor α (TNFα) and TNF signaling pathway display an antitumor activity in preclinical models and in tumor patients. However, TNFα exhibits no significance for glioma clinical prognosis based on Glioma Genome Atlas database. This study aimed to explore whether TNFα of tumor microenvironment maintains self-renewal of GSCs and promotes worse prognosis in glioma patient.

Methods: Spatial transcriptomics, immunoblotting, sphere formation assay, extreme limiting dilution, and gene expression analysis were used to determine the role of TNFα on GSC's self-renewal. Mass spectrometry, RNA-sequencing detection, bioinformatic analyses, qRT-RNA, immunofluorescence, immunohistochemistry, single cell RNA Sequencing, in vitro and in vivo models were used to uncover the mechanism of TNFα-induced GSC self-renewal.

Results: Low level of TNFα displays a promoting effect on GSC self-renewal and worse glioma prognosis. Mechanistically, Vasorin (VASN) mediated TNFα-induced self-renewal by potentiating glycolysis. Lactate produced by glycolysis inhibits the TNFα secretion of tumor-associated macrophages (TAMs) and maintains TNFα in a low level.

Conclusions: TNFα-induced GSC self-renewal mediated by VASN provides a possible explanation for the failures of endogenous TNFα effect on GBM. Combination of targeting VASN and TNFα anti-tumor effect may be an effective approach for treating GBM.

Keywords
Glioma stem cell; Glycolysis; Tumor necrosis factor α; Tumor-associated macrophages.
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