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Quantitative Immunohistochemistry of the Cellular Microenvironment in Patient Glioblastoma Resections
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M2-like tumor-associated macrophages transmit exosomal miR-27b-3p and maintain glioblastoma stem-like cell properties

Guifang Zhao1,2, Lijuan Ding3, Hongquan Yu4

  • 1The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, 511518, People's Republic of China.

Cell Death Discovery
|August 4, 2022
PubMed

Insights

Tumor-associated macrophages release exosomes containing miR-27b-3p, which promote glioblastoma stem cell (GSC) growth. This microRNA targets the MLL4/PRDM1/IL-33 pathway, enhancing GSC tumorigenicity and stem-like properties.

Area of Science:

  • Oncology
  • Cell Biology
  • Molecular Biology

Background:

  • Exosomes mediate intercellular communication, influencing cancer phenotypes.
  • MicroRNAs (miRs) within exosomes play a role in glioblastoma stem cell (GSC) properties.
  • The specific function of exosomal miR-27b-3p in GSCs, particularly its origin from M2 tumor-associated macrophages (M2-TAMs), requires elucidation.

Purpose of the Study:

  • To investigate the impact of M2-TAM-derived exosomal miR-27b-3p on GSC function and glioblastoma (GBM) tumorigenicity.
  • To identify the molecular mechanisms, including the miR-27b-3p/MLL4/PRDM1 axis, involved in this interaction.
  • To validate findings in both in vitro and in vivo GBM models.

Main Methods:

  • Isolation of GSCs and M2-TAMs from clinical GBM specimens using fluorescence-activated cell sorting (FACS).
  • Separation and characterization of exosomes derived from M2-TAMs.
  • In vitro gain- and loss-of-function assays to assess the role of exosomal miR-27b-3p and the MLL4/PRDM1 axis in GSC phenotypes.
  • In vivo xenograft tumor model establishment for evaluating therapeutic efficacy.
  • Dual-luciferase and ChIP assays to validate molecular interactions.

Main Results:

  • M2-TAM-derived exosomes significantly promoted stem-like properties and viability of GSCs in vitro.
  • Inhibition of miR-27b-3p in M2-TAMs reduced exosome transfer to GSCs, diminishing GSC viability and in vivo tumor growth.
  • miR-27b-3p was found to target MLL4, which positively regulated PRDM1 expression via enhancer methylation, ultimately reducing IL-33 expression.
  • The miR-27b-3p/MLL4/PRDM1/IL-33 axis was confirmed to be crucial for maintaining GSC stem-like function.

Conclusions:

  • M2-TAM-derived exosomal miR-27b-3p enhances glioblastoma tumorigenicity by activating the IL-33 pathway through the MLL4/PRDM1 axis.
  • This study identifies a novel mechanism of intercellular communication in the GBM microenvironment that promotes cancer stem cell properties.
  • Targeting exosomal miR-27b-3p or its downstream effectors presents a potential therapeutic strategy for glioblastoma.

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