Stress-induced pro-inflammatory glioblastoma stem cells secrete TNFAIP6 to enhance tumor growth and induce suppressive macrophages.

in Developmental cell by Danling Gu, Lang Hu, Kailin Yang, Wei Yuan, Danyang Shan, Jiancheng Gao, Jiahuang Li, Ryan C Gimple, Deobrat Dixit, Zhe Zhu, Daqi Li, Qiulian Wu, Zhumei Shi, Yingyi Wang, Ningwei Zhao, Kun Yang, Junfei Shao, Fan Lin, Qianghu Wang, Guangfu Jin, Yun Chen, Xu Qian, Zhibin Hu, Chaojun Li, Nu Zhang, Yongping You, Jian Liu, Qian Zhang, Junxia Zhang, Jeremy N Rich, Xiuxing Wang

TLDR

  • The study identifies TNFAIP6 as a key player in the communication between glioblastoma stem cells and pro-inflammatory macrophages, suggesting it as a potential therapeutic target for glioblastoma.

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.

Overview

  • This study investigates the relationship between glioblastoma stem cells (GSCs) and pro-inflammatory macrophages (pTAMs) in human glioblastoma.
  • The study aims to understand the underlying mechanism of GSCs facing pro-inflammatory stress and its role in tumor development.
  • The researchers focus on TNFAIP6, a protein involved in the response of GSCs to pro-inflammatory stress, and its potential as a therapeutic target for glioblastoma.

Comparative Analysis & Findings

  • The study shows that pro-inflammatory stress from pTAMs maintains GSC proliferation and self-renewal in human glioblastoma.
  • TNFAIP6, a responder to pro-inflammatory stress in patient-derived GSCs, promotes tumor growth by binding EGF and prolonging EGF receptor-PI3K-AKT signaling activation.
  • 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.

Implications and Future Directions

  • The study suggests that TNFAIP6 is an effective target for glioblastoma therapy, providing new insights into the pathogenesis of glioblastoma and potential therapeutic strategies.
  • Further research is needed to fully understand the mechanisms of TNFAIP6 in glioblastoma and to explore its potential as a therapeutic target.
  • The study highlights the importance of considering the inflammatory microenvironment and its interaction with glioblastoma stem cells in future research and clinical trials.
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