2. Academic Validation
  3. STAT3-controlled CHI3L1/SPP1 positive feedback loop demonstrates the spatial heterogeneity and immune characteristics of glioblastoma

STAT3-controlled CHI3L1/SPP1 positive feedback loop demonstrates the spatial heterogeneity and immune characteristics of glioblastoma

  • Dev Cell. 2025 Jun 23;60(12):1751-1767.e9. doi: 10.1016/j.devcel.2025.01.014.
Wanli Yu 1,  Shikai Gui 1,  Lunshan Peng 1,  Haitao Luo 2,  Jiabao Xie 1,  Juexian Xiao 2,  Yimuran Yilamu 3,  Yi Sun 3,  Shihao Cai 1,  Zujue Cheng 4,  Zhennan Tao 5
Affiliations

Affiliations

  • 1 Department 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.
  • 2 Department of Neurosurgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, Jiangxi, China.
  • 3 Department of Neurosurgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, Jiangsu, China.
  • 4 Department of Neurosurgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, Jiangxi, China. Electronic address: juejue@126.com.
  • 5 Department of Neurosurgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, Jiangsu, China; Neurosurgical Institute, Nanjing University, Nanjing 210008, Jiangsu, China. Electronic address: drtaozn@njglyy.com.
PMID: 39933531 DOI: 10.1016/j.devcel.2025.01.014
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.

Keywords

CHI3L1, SPP1; PMT; glioblastoma; macrophages; scMulti-omics.

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