Transfer of MicroRNA via Macrophage-Derived Extracellular Vesicles Promotes Proneural-to-Mesenchymal Transition in Glioma Stem Cells
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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.
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“Depletion of monocytes, as well as their conversion to macrophages, has been shown to promote PMT [96,97], through the stimulation of intratumoral neutrophils flux and neutrophil-derived TNF-α which, in turn, increases hypoxia in PDGFB-driven GBMs and fosters PMT [96].”
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“Meanwhile, miR-22 transferred from TAMs to glioma stem cells was able to promote mesenchymal phenotypes and induce radiotherapy resistance by targeting the chromodomain helicase DNA-binding protein 7 (CHD7), a chromodomain enzyme that maintains the proneural phenotype in glioblastoma [26].”
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“45 Overall, the miRNA-dominated cargo of M2-derived extracellular vesicles cooperates across multiple central pathways: on one hand, they open metastatic channels through vascular permeability, angiogenesis, and VM; on the other hand, they systematically activate pathways such as PTEN/Akt,…”
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“In primary or recurrent GBMs, studies have reported factors that lead to PMT, such as (1) cell-intrinsic factors (e.g., transcription factors), (2) cell-extrinsic factors: tumor immune microenvironment (e.g., macrophages) [46, 47], and (3) cytotoxic therapy (e.g., radiotherapy/chemotherapy) [48].”
- Authors
- Zhang, Z., Xu, J., Chen, Z., Wang, H., Xue, H., Yang, C., Guo, Q., Qi, Y., Guo, X., Qian, M., Wang, S., Qiu, W., Gao, X., Zhao, R., Guo, X., & Li, G.
- Affiliations
- Shandong University (CN)
- ORCID
- Venue
- Cancer Immunology Research
- Published
- 2020-07-01
- Volume
- 8
- Issue
- 7
- Pages
- 966-981
- ISSN
- 2326-6066 (ISSN-L)
- 2326-6074
- OpenAlex
- W3023468082
- Semantic Scholar
- 70d1701f96810851cff19d8a443db499c029c6da
- Cited by
- 93
- References
- 42
- Citations by year
- 2026: 7 · 2025: 15 · 2024: 11 · 2023: 17 · 2022: 24 · 2021: 15 · 2020: 4
- FWCI
- 4.22
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cancer Immunology Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (81571284, 81874083, 81702468, 81802966, 81902540)
- National Natural Science Foundation of Shandong Province of China (2017CXGC1203, 2017G006012, ZR2019BH057)
- Taishan Scholars of Shandong Province of China (ts201511093)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Keywords
- proneural-to-mesenchymal transition, glioma stem cells, glioblastoma, tumor-associated macrophages, extracellular vesicles, microRNA transfer, miR-27a-3p, miR-22-3p, miR-221-3p, CHD7, radiotherapy resistance, STAT3 signaling, tumor microenvironment
- MeSH terms
- Extracellular Vesicles, Animals, Brain Neoplasms, Cells, Cultured, DNA Helicases, DNA-Binding Proteins, Glioma, Humans, Macrophages, Mice, Nude, Radiation Protection, Neoplastic Stem Cells, Gene Expression Regulation, Neoplastic, Spheroids, Cellular, Xenograft Model Antitumor Assays, MicroRNAs, Cell Proliferation, Mice, Mesenchymal Stem Cells
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