Journal article
Dual Role of CXCL8 in Maintaining the Mesenchymal State of Glioblastoma Stem Cells and M2-Like Tumor-Associated Macrophages
Clinical cancer research, Vol.29(18), pp.3779-3792
09/15/2023
DOI: 10.1158/1078-0432.CCR-22-3273
PMID: 37439870
Abstract
The dynamic interplay between glioblastoma stem cells (GSC) and tumor-associated macrophages (TAM) sculpts the tumor immune microenvironment (TIME) and promotes malignant progression of glioblastoma (GBM). However, the mechanisms underlying this interaction are still incompletely understood. Here, we investigate the role of CXCL8 in the maintenance of the mesenchymal state of GSC populations and reprogramming the TIME to an immunosuppressive state.
We performed an integrative multi-omics analyses of RNA sequencing, GBM mRNA expression datasets, immune signatures, and epigenetic profiling to define the specific genes expressed in the mesenchymal GSC subsets. We then used patient-derived GSCs and a xenograft murine model to investigate the mechanisms of tumor-intrinsic and extrinsic factor to maintain the mesenchymal state of GSCs and induce TAM polarization.
We identified that CXCL8 was preferentially expressed and secreted by mesenchymal GSCs and activated PI3K/AKT and NF-κB signaling to maintain GSC proliferation, survival, and self-renewal through a cell-intrinsic mechanism. CXCL8 induced signaling through a CXCR2-JAK2/STAT3 axis in TAMs, which supported an M2-like TAM phenotype through a paracrine, cell-extrinsic pathway. Genetic- and small molecule-based inhibition of these dual complementary signaling cascades in GSCs and TAMs suppressed GBM tumor growth and prolonged survival of orthotopic xenograft-bearing mice.
CXCL8 plays critical roles in maintaining the mesenchymal state of GSCs and M2-like TAM polarization in GBM, highlighting an interplay between cell-autonomous and cell-extrinsic mechanisms. Targeting CXCL8 and its downstream effectors may effectively improve GBM treatment.
Details
- Title: Subtitle
- Dual Role of CXCL8 in Maintaining the Mesenchymal State of Glioblastoma Stem Cells and M2-Like Tumor-Associated Macrophages
- Creators
- Wei Yuan - Yancheng First People's HospitalQian Zhang - Nanjing Medical UniversityDanling Gu - Nanjing Medical UniversityChenfei Lu - Nanjing Medical UniversityDeobrat Dixit - University of California, San DiegoRyan C Gimple - Case Western Reserve UniversityYisu Gao - Yancheng First People's HospitalJiancheng Gao - Nanjing Medical UniversityDaqi Li - Nanjing Medical UniversityDanyang Shan - Nanjing Medical UniversityLang Hu - Nanjing Medical UniversityLu Li - Nanjing Medical UniversityYangqing Li - Model Animal Research CenterShusheng Ci - Nanjing Medical UniversityHao You - Nanjing Medical UniversityLinping Yan - Nanjing Medical UniversityKexin Chen - Nanjing Medical UniversityNingwei Zhao - China Exposomics Institute, Shanghai, ChinaChuanhai Xu - Yancheng First People's HospitalJianyun Lan - Yancheng First People's HospitalDong Liu - Nantong UniversityJunxia Zhang - Nanjing Medical UniversityZhumei Shi - Nanjing Medical UniversityQiulian Wu - University of California, San DiegoKailin Yang - Cleveland ClinicLinjie Zhao - University of California, San DiegoZhixin Qiu - Fudan UniversityDeguan Lv - University of California, San DiegoWei Gao - Nanjing Medical UniversityHui Yang - Huashan HospitalFan Lin - Nanjing Medical UniversityQianghu Wang - Jiangsu Cancer HospitalJianghong Man - National Center of Biomedical AnalysisChaojun Li - Nanjing UniversityWeiwei Tao - Huazhong Agricultural UniversitySameer Agnihotri - University of PittsburghXu Qian - Jiangsu Cancer HospitalStephen C Mack - St. Jude Children's Research HospitalNu Zhang - Sun Yat-sen UniversityYongping You - Jiangsu Province HospitalJeremy N Rich - University of California, San DiegoGuan Sun - Yancheng First People's HospitalXiuxing Wang - Nanjing Medical University
- Resource Type
- Journal article
- Publication Details
- Clinical cancer research, Vol.29(18), pp.3779-3792
- DOI
- 10.1158/1078-0432.CCR-22-3273
- PMID
- 37439870
- ISSN
- 1078-0432
- eISSN
- 1557-3265
- Language
- English
- Date published
- 09/15/2023
- Academic Unit
- Radiation Oncology
- Record Identifier
- 9984696719502771
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