Clusterin-mediated polarization of M2 macrophages: a mechanism of temozolomide resistance in glioblastoma stem cells.

in Stem cell research & therapy by Jianping Wen, Xia Wu, Zhicheng Shu, Dongxu Wu, Zonghua Yin, Minglong Chen, Kun Luo, Kebo Liu, Yulong Shen, Yi Le, Qingxia Shu

TLDR

  • This study reveals a novel resistance mechanism in glioblastoma involving glioblastoma stem cells, M2-type macrophages, and Clusterin-containing extracellular vesicles, and suggests that targeting this pathway could potentially reverse resistance mechanisms.

Abstract

Glioblastoma remains one of the most lethal malignancies, largely due to its resistance to standard chemotherapy such as temozolomide. This study investigates a novel resistance mechanism involving glioblastoma stem cells (GSCs) and the polarization of M2-type macrophages, mediated by the extracellular vesicle (EV)-based transfer of Clusterin. Using 6-week-old male CD34humanized huHSC-(M-NSG) mice (NM-NSG-017) and glioblastoma cell lines (T98G and U251), we demonstrated that GSC-derived EVs enriched with Clusterin induce M2 macrophage polarization, thereby enhancing temozolomide resistance in glioblastoma cells. Single-cell and transcriptome sequencing revealed close interactions between GSCs and M2 macrophages, highlighting Clusterin as a key mediator. Our findings indicate that Clusterin-rich EVs from GSCs drive glioblastoma cell proliferation and resistance to temozolomide by modulating macrophage phenotypes. Targeting this pathway could potentially reverse resistance mechanisms, offering a promising therapeutic approach for glioblastoma. This study not only sheds light on a critical pathway underpinning glioblastoma resistance but also lays the groundwork for developing therapies targeting the tumor microenvironment. Our results suggest a paradigm shift in understanding glioblastoma resistance, emphasizing the therapeutic potential of disrupting EV-mediated communication in the tumor microenvironment.

Overview

  • This study investigates a novel resistance mechanism in glioblastoma involving glioblastoma stem cells (GSCs), M2-type macrophages, and Clusterin-containing extracellular vesicles (EVs).
  • The study used CD34humanized huHSC-(M-NSG) mice and glioblastoma cell lines (T98G and U251) to demonstrate that GSC-derived EVs enriched with Clusterin induce M2 macrophage polarization, enhancing temozolomide resistance in glioblastoma cells.
  • The primary objective is to understand the role of Clusterin-rich EVs from GSCs in glioblastoma cell proliferation and resistance to temozolomide, and to identify potential therapeutic targets in this pathway.

Comparative Analysis & Findings

  • Single-cell and transcriptome sequencing revealed close interactions between GSCs and M2 macrophages, highlighting Clusterin as a key mediator in glioblastoma resistance.
  • GSC-derived EVs enriched with Clusterin induce M2 macrophage polarization, enhancing temozolomide resistance in glioblastoma cells.
  • The study suggests that targeting this pathway could potentially reverse resistance mechanisms, offering a promising therapeutic approach for glioblastoma.

Implications and Future Directions

  • This study sheds light on a critical pathway underpinning glioblastoma resistance and lays the groundwork for developing therapies targeting the tumor microenvironment.
  • Our results suggest a paradigm shift in understanding glioblastoma resistance, emphasizing the therapeutic potential of disrupting EV-mediated communication in the tumor microenvironment.
  • Future studies could focus on identifying small molecule inhibitors or RNA-based therapies targeting Clusterin and its downstream effectors to develop novel treatment strategies for glioblastoma.
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