Hypoxia-induced TGFBI maintains glioma stem cells by stabilizing EphA2.

in Theranostics by Zirong Chen, Junhong Wang, Peng Peng, Guohao Liu, Minhai Dong, Xiaolin Zhang, Yang Zhang, Xue Yang, Lijun Wan, Wang Xiang, Suojun Zhang, Bin Zhang, Qiuxia Wu, Xingjiang Yu, Feng Wan

TLDR

  • The study shows that TGFBI helps GSCs survive and grow in the hypoxic environment.
  • The study found that TGFBI is important for GSCs to keep their stem cell properties.
  • The study suggests that targeting TGFBI and EphA2 could be a new way to treat GBM.

Abstract

Glioma stem cells (GSCs) have emerged as pivotal drivers of tumor malignancy, sustained by various microenvironmental factors, including immune molecules and hypoxia. In our previous study, we elucidated the significant role of transforming growth factor beta-induced protein (TGFBI), a protein secreted by M2-like tumor-associated macrophages, in promoting the malignant behavior of glioblastoma (GBM) under normoxic conditions. Building upon these findings, the objective of this study was to comprehensively explore the crucial role and underlying mechanisms of autocrine TGFBI in GSCs under hypoxic conditions.We quantified TGFBI expression in glioma specimens and datasets.andassays were employed to investigate the effects of TGFBI on sustaining self-renewal and tumorigenesis of GSCs under hypoxia. RNA-seq and LC-MS/MS were conducted to explore TGFBI signaling mechanisms.TGFBI is preferentially expressed in GSCs under hypoxic conditions. Targeting TGFBI impair GSCs self-renewal and tumorigenesis. Mechanistically, TGFBI was upregulated by HIF1α in GSCs and predominantly activates the AKT-c-MYC signaling pathway in GSCs by stabilizing the EphA2 protein through preventing its degradation.TGFBI plays a crucial role in maintaining the stem cell properties of GSCs in the hypoxic microenvironment. Targeting the TGFBI/EphA2 axis emerges as a promising and innovative strategy for GBM treatment, with the potential to improve the clinical outcomes of patients.

Overview

  • The study aims to explore the crucial role and underlying mechanisms of autocrine TGFBI in GSCs under hypoxic conditions.
  • TGFBI is preferentially expressed in GSCs under hypoxic conditions.
  • The study quantifies TGFBI expression in glioma specimens and datasets.

Comparative Analysis & Findings

  • Targeting TGFBI impairs GSCs self-renewal and tumorigenesis.
  • TGFBI is upregulated by HIF1α in GSCs and predominantly activates the AKT-c-MYC signaling pathway in GSCs by stabilizing the EphA2 protein through preventing its degradation.
  • The study identifies the TGFBI/EphA2 axis as a promising and innovative strategy for GBM treatment.

Implications and Future Directions

  • The study highlights the importance of TGFBI in maintaining the stem cell properties of GSCs in the hypoxic microenvironment.
  • Targeting the TGFBI/EphA2 axis emerges as a promising and innovative strategy for GBM treatment, with the potential to improve the clinical outcomes of patients.
  • Future research should focus on developing targeted therapies that specifically target the TGFBI/EphA2 axis in GSCs.
Read Full Article