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Characterization of Immune Cell-derived Extracellular Vesicles and Studying Functional Impact on Cell Environment
Published on: June 2, 2020
Transfer of MicroRNA via Macrophage-Derived Extracellular Vesicles Promotes Proneural-to-Mesenchymal Transition in
Zongpu Zhang1,2,3, Jianye Xu1,2,3, Zihang Chen1,2,3
1Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
Abstract:
Proneural-to-mesenchymal transition (PMT) is a common process in glioblastoma (GBM) progression that leads to increased radiotherapy resistance. However, the mechanism underlying PMT is poorly understood. Here, we found that tumor-associated macrophages triggered PMT in glioma stem cells (GSC) via small extracellular vesicles (sEV). sEVs from monocyte-derived macrophages transferred miR-27a-3p, miR-22-3p, and miR-221-3p to GSCs, and these miRNAs promoted several mesenchymal phenotypes in proneural (PN) GSCs by simultaneously targeting CHD7 We found that CHD7 played a critical role in the maintenance of the PN phenotype, and CHD7 knockdown significantly promoted PMT in GSCs via the RelB/P50 and p-STAT3 pathways. The induction of PMT by sEVs containing miR-27a-3p, miR-22-3p, and miR-221-3p in a xenograft nude mouse model exacerbated radiotherapy resistance and thus decreased the benefits of radiotherapy. Collectively, these findings identified macrophage-derived sEVs as key regulators of PMT in GSCs and demonstrated that CHD7 is a novel inhibitor of PMT.
Insights
Tumor-associated macrophages promote glioblastoma progression and radiotherapy resistance via small extracellular vesicles. These vesicles transfer miRNAs that drive proneural-to-mesenchymal transition by targeting CHD7, a key inhibitor of this process.
Area of Science:
- Oncology
- Cell Biology
- Molecular Medicine
Background:
- Proneural-to-mesenchymal transition (PMT) is a critical mechanism in glioblastoma (GBM) development, contributing to therapeutic resistance.
- The precise molecular pathways governing PMT in GBM remain incompletely understood.
Purpose of the Study:
- To elucidate the role of tumor-associated macrophages (TAMs) and their secreted factors in mediating PMT in glioma stem cells (GSCs).
- To identify the specific molecular components transferred by TAMs that induce PMT and to investigate the downstream signaling pathways involved.
Main Methods:
- Isolation and characterization of small extracellular vesicles (sEVs) from monocyte-derived macrophages.
- Analysis of miRNA content within sEVs and their transfer to GSCs.
- Assessment of PMT induction, gene expression changes (targeting CHD7), and pathway activation (RelB/P50, p-STAT3) in GSCs.
- Evaluation of the impact of sEV-induced PMT on radiotherapy resistance in a xenograft mouse model.
Main Results:
- TAM-derived sEVs were found to trigger PMT in proneural (PN) GSCs.
- Specific miRNAs (miR-27a-3p, miR-22-3p, miR-221-3p) transferred via sEVs target CHD7, promoting mesenchymal phenotypes.
- CHD7 knockdown was shown to induce PMT through the RelB/P50 and p-STAT3 pathways.
- sEV-mediated PMT in vivo exacerbated radiotherapy resistance in a mouse model.
Conclusions:
- Macrophage-derived sEVs are key regulators of PMT in GSCs, driving glioblastoma progression and radioresistance.
- CHD7 acts as a novel inhibitor of PMT, and its downregulation by specific miRNAs facilitates mesenchymal transition.
- Targeting the macrophage-sEV-miRNA-CHD7 axis presents a potential therapeutic strategy to overcome GBM radioresistance.
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