Transfer of MicroRNA via Macrophage-Derived Extracellular Vesicles Promotes Proneural-to-Mesenchymal Transition in Glioma Stem Cells

• Published in: Cancer immunology research Vol. 8; no. 7; p. 966
• Main Authors: Zhang, Zongpu, Xu, Jianye, Chen, Zihang, Wang, Huizhi, Xue, Hao, Yang, Chunlei, Guo, Qindong, Qi, Yanhua, Guo, Xiaofan, Qian, Mingyu, Wang, Shaobo, Qiu, Wei, Gao, Xiao, Zhao, Rongrong, Guo, Xing, Li, Gang
• Format: Journal Article
• Language: English
• Published: United States 01.07.2020
• Subjects: Animals; Brain Neoplasms - genetics; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Brain Neoplasms - radiotherapy; Cell Proliferation; Cells, Cultured; DNA Helicases - metabolism; DNA-Binding Proteins - metabolism; Extracellular Vesicles - genetics; Extracellular Vesicles - metabolism; Gene Expression Regulation, Neoplastic; Glioma - genetics; Glioma - metabolism; Glioma - pathology; Glioma - radiotherapy; Humans; Macrophages - metabolism; Mesenchymal Stem Cells - metabolism; Mesenchymal Stem Cells - pathology; Mice; Mice, Nude; MicroRNAs - genetics; MicroRNAs - metabolism; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Radiation Protection; Spheroids, Cellular; Xenograft Model Antitumor Assays
• ISSN: 2326-6074
• DOI: 10.1158/2326-6066.cir-19-0759

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 , and to GSCs, and these miRNAs promoted several mesenchymal phenotypes in proneural (PN) GSCs by simultaneously targeting We found that CHD7 played a critical role in the maintenance of the PN phenotype, and knockdown significantly promoted PMT in GSCs via the RelB/P50 and p-STAT3 pathways. The induction of PMT by sEVs containing , and 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.