CCL2 mediated IKZF1 expression promotes M2 polarization of glioma-associated macrophages through CD84-SHP2 pathway

• Published in: Oncogene 2024-08, Vol.43 (36), p.2737-2749
• Main Authors: Song, Yifu, Zhang, Yaochuan, Wang, Zixun, Lin, Yibin, Cao, Xu, Han, Xiaodi, Li, Guangyu, Hou, Ana, Han, Sheng
• Format: Article
• Language: English
• Subjects: 13/31; 38/1; 38/109; 38/89; 631/67/327; 631/67/71; Angiogenesis; Animal models; Animals; Antigens, CD - genetics; Antigens, CD - metabolism; Apoptosis; Bioinformatics; Brain Neoplasms - genetics; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Cell Biology; Cell culture; Cell Line, Tumor; Cell proliferation; Chemokine CCL2 - genetics; Chemokine CCL2 - metabolism; Chemotherapy; Gene Expression Regulation, Neoplastic; Glioma; Glioma - genetics; Glioma - metabolism; Glioma - pathology; Glioma cells; Human Genetics; Humans; Ikaros Transcription Factor - genetics; Ikaros Transcription Factor - metabolism; Immunosuppression; Internal Medicine; Macrophages; Macrophages - metabolism; Macrophages - pathology; Malignancy; Medicine; Medicine & Public Health; Mice; Microenvironments; Molecular modelling; Monocyte chemoattractant protein 1; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Oncology; Phenotypes; Polarization; Protein Tyrosine Phosphatase, Non-Receptor Type 11 - genetics; Protein Tyrosine Phosphatase, Non-Receptor Type 11 - metabolism; Signal Transduction - genetics; Tumor Microenvironment - genetics; Tumor-Associated Macrophages - metabolism; Tumor-Associated Macrophages - pathology; Tumors
• ISSN: 0950-9232; 1476-5594; 1476-5594
• DOI: 10.1038/s41388-024-03118-w

The proneural-mesenchymal (PN-MES) transformation of glioma stem cells (GSCs) can significantly increase proliferation, invasion, chemotherapy tolerance, and recurrence. M2-like polarization of tumor-associated macrophages (TAMs) has a strong immunosuppressive effect, promoting tumor malignancy and angiogenesis. There is limited understanding on the interactions between GSCs and TAMs as well as their associated molecular mechanisms. In the present study, bioinformatics analysis, GSC and TAM co-culture, determination of TAM polarization phenotypes, and other in vitro experiments confirmed that CCL2 secreted by MES-GSCs promotes TAM-M2 polarization via the IKZF1-CD84-SHP2 pathway and PN-MES transformation of GSCs via the IKZF1-LRG1 pathway in TAMs. IKZF1 inhibitors could significantly reduce tumor volumes in animal glioma models and improve survival, as well as suppress TAM-M2 polarization and the GSC malignant phenotype. The results of this study indicate the important interaction between TAMs and GSCs in the glioma microenvironment as well as its role in tumor progression. The findings also suggest a novel target for follow-up clinical transformation research on the regulation of TAM function and GSCs malignant phenotype.