Super-enhancer-driven LIF promotes the mesenchymal transition in glioblastoma by activating ITGB2 signaling feedback in microglia

作者：Han Xie, Yan‐Yi Jiang, Yufei Xiang, Baoming Wu, Jiajia Zhao, Ruixiang Huang, Mengting Wang, Yunlong Wang, Jun Liu, Dejun Wu, Dasheng Tian, Erbao Bian · 发表于：Neuro-Oncology · 年份：2024 · DOI：10.1093/neuonc/noae065 · 被引用次数：21 · 研究领域：Glioma Diagnosis and Treatment、Neuroinflammation and Neurodegeneration Mechanisms、Cytokine Signaling Pathways and Interactions

BACKGROUND: The mesenchymal (MES) subtype of glioblastoma (GBM) is believed to be influenced by both cancer cell-intrinsic alterations and extrinsic cellular interactions, yet the underlying mechanisms remain unexplored. METHODS: Identification of microglial heterogeneity by bioinformatics analysis. Transwell migration, invasion assays, and tumor models were used to determine gene function and the role of small molecule inhibitors. RNA sequencing, chromatin immunoprecipitation, and dual-luciferase reporter assays were performed to explore the underlying regulatory mechanisms. RESULTS: We identified the inflammatory microglial subtype of tumor-associated microglia (TAM) and found that its specific gene integrin beta 2 (ITGB2) was highly expressed in TAM of MES GBM tissues. Mechanistically, the activation of ITGB2 in microglia promoted the interaction between the SH2 domain of STAT3 and the cytoplasmic domain of ITGB2, thereby stimulating the JAK1/STAT3/IL-6 signaling feedback to promote the MES transition of GBM cells. Additionally, microglia communicated with GBM cells through the interaction between the receptor ITGB2 on microglia and the ligand ICAM-1 on GBM cells, while an increased secretion of ICAM-1 was induced by the proinflammatory cytokine leukemia inhibitory factor (LIF). Further studies demonstrated that inhibition of cyclin-dependent kinase 7 substantially reduced the recruitment of SNW1 to the super-enhancer of LIF, resulting in transcriptional inhibition of LIF....