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Updated: May 28, 2025
Isolation and Flow Cytometric Analysis of Glioma-infiltrating Peripheral Blood Mononuclear Cells
Published on: November 28, 2015
STAT3-controlled CHI3L1/SPP1 positive feedback loop demonstrates the spatial heterogeneity and immune characteristics
Wanli Yu1, Shikai Gui1, Lunshan Peng1
1Department of Neurosurgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, Jiangxi, China; Jiangxi Province Key Laboratory of Neurological Diseases, Nanchang University, Nanchang 330006, Jiangxi, China; JXHC key Laboratory of Neurological Medicine, Nanchang University, Nanchang 330006, Jiangxi, China; Institute of Neuroscience, Nanchang University, Nanchang 330006, Jiangxi, China.
Abstract:
Proneural-mesenchymal transition (PMT) is a phenotypic alteration and contributes to the malignant progression of glioblastoma (GBM). Macrophages, as a main infiltrating component of the tumor immune microenvironment (TIM), control the biological processes of PMT; however, the mechanisms driving this process remain largely unknown. Here, the overall landscape of tumor and nontumor cells was described by scMulti-omics technology. Then, we demonstrated that chitinase-3-like protein 1 (CHI3L1) played a critical role in maintaining mesenchymal (MES) status and reprogramming macrophage phenotype using C57BL/6 and NSG mice models derived from PN20 cells. Mechanistically, osteopontin (OPN)/ITGB1 maintained the activation of nuclear factor κB (NF-κB) and signal transducer and activator of transcription 3 (STAT3) pathways by establishing a positive feedback loop with the CHI3L1-STAT3 axis, resulting in PMT. CHI3L1 enhanced the phosphorylation, nuclear localization, and transcriptional activity of STAT3 via directly binding its coiled-coil domain (CCD). Importantly, we screened and validated that hygromycin B (HB), an inhibitor of the STAT3-CCD domain, disrupted the CHI3L1-STAT3 interaction, thereby reducing the tumor burden in vitro and in vivo.
