Glioma stem cell‐derived exosomes induce the transformation of astrocytes via the miR‐3065‐5p/DLG2 signaling axis

• Published in: Glia 2024-05, Vol.72 (5), p.857-871
• Main Authors: Li, Haoran, Zhu, Jianjun, Liu, Xinglei, Liu, Liang, Huang, Shilu, Wu, Anyi, Xu, Zhipeng, Zhang, Xiaopei, Li, Zengyang, Ni, Fan, Liu, Lijun, Dong, Jun
• Format: Article
• Language: English
• Subjects: Astrocytes; Astrocytes - metabolism; Carcinogenesis - genetics; CD44 antigen; Cell Proliferation; DLG2; exosomal miR‐3065‐5p; Exosomes; Exosomes - metabolism; Glioblastoma; Glioblastoma - pathology; Glioma; Glioma - pathology; Glioma cells; glioma stem cell; Guanylate Kinases - metabolism; Humans; Microenvironments; MicroRNAs; MicroRNAs - genetics; MicroRNAs - metabolism; miRNA; Neoplastic Stem Cells - metabolism; Polymerase chain reaction; Postsynaptic density proteins; Reverse transcription; Stem cells; Temozolomide; Temozolomide - metabolism; Temozolomide - pharmacology; Tenascin; transformation; Tumor Microenvironment; Tumor Suppressor Proteins - metabolism; Tumorigenesis; Tumors; tumor‐associated astrocyte
• ISSN: 0894-1491; 1098-1136; 1098-1136
• DOI: 10.1002/glia.24506

Tumor‐associated astrocytes (TAAs) in the glioblastoma microenvironment play an important role in tumor development and malignant progression initiated by glioma stem cells (GSCs). In the current study, normal human astrocytes (NHAs) were cultured and continuously treated with GSC‐derived exosomes (GSC‐EXOs) induction to explore the mechanism by which GSCs affect astrocyte remodeling. This study revealed that GSC‐EXOs can induce the transformation of NHAs into TAAs, with relatively swollen cell bodies and multiple extended processes. In addition, high proliferation, elevated resistance to temozolomide (TMZ), and increased expression of TAA‐related markers (TGF‐β, CD44, and tenascin‐C) were observed in the TAAs. Furthermore, GSC‐derived exosomal miR‐3065‐5p could be delivered to NHAs, and miR‐3065‐5p levels increased significantly in TAAs, as verified by miRNA expression profile sequencing and Reverse transcription polymerase chain reaction. Overexpression of miR‐3065‐5p also enhanced NHA proliferation, elevated resistance to TMZ, and increased the expression levels of TAA‐related markers. In addition, both GSC‐EXO‐induced and miR‐3065‐5p‐overexpressing NHAs promoted tumorigenesis of GSCs in vivo. Discs Large Homolog 2 (DLG2, downregulated in glioblastoma) is a direct downstream target of miR‐3065‐5p in TAAs, and DLG2 overexpression could partially reverse the transformation of NHAs into TAAs. Collectively, these data demonstrate that GSC‐EXOs induce the transformation of NHAs into TAAs via the miR‐3065‐5p/DLG2 signaling axis and that TAAs can further promote the tumorigenesis of GSCs. Thus, precisely blocking the interactions between astrocytes and GSCs via exosomes may be a novel strategy to inhibit glioblastoma development, but more in‐depth mechanistic studies are still needed. Main Points Glioma stem cell‐derived exosomes induce the transformation of astrocytes into tumor‐associated astrocytes. Glioma stem cell‐astrocyte crosstalk is regulated by miR‐3065‐5p/DLG2 signaling axis. Transformed astrocytes further promote tumorigenesis.