Differentiated glioblastoma cells accelerate tumor progression by shaping the tumor microenvironment via CCN1-mediated macrophage infiltration

被引:0
作者
Atsuhito Uneda
Kazuhiko Kurozumi
Atsushi Fujimura
Kentaro Fujii
Joji Ishida
Yosuke Shimazu
Yoshihiro Otani
Yusuke Tomita
Yasuhiko Hattori
Yuji Matsumoto
Nobushige Tsuboi
Keigo Makino
Shuichiro Hirano
Atsunori Kamiya
Isao Date
机构
[1] Okayama University Graduate School of Medicine,Department of Neurological Surgery
[2] Dentistry,Department of Cellular Physiology
[3] and Pharmaceutical Sciences,Department of Neurosurgery
[4] Okayama University Graduate School of Medicine,Neutron Therapy Research Center
[5] Dentistry and Pharmaceutical Sciences,undefined
[6] Hamamatsu University School of Medicine,undefined
[7] Okayama University,undefined
来源
Acta Neuropathologica Communications | / 9卷
关键词
Differentiated glioblastoma cell; Glioblastoma stem cell; CCN1; YAP/TAZ; TEAD; Mesenchymal subtype; Macrophage; Microenvironment; Glioma; Glioblastoma;
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学科分类号
摘要
Glioblastoma (GBM) is the most lethal primary brain tumor characterized by significant cellular heterogeneity, namely tumor cells, including GBM stem-like cells (GSCs) and differentiated GBM cells (DGCs), and non-tumor cells such as endothelial cells, vascular pericytes, macrophages, and other types of immune cells. GSCs are essential to drive tumor progression, whereas the biological roles of DGCs are largely unknown. In this study, we focused on the roles of DGCs in the tumor microenvironment. To this end, we extracted DGC-specific signature genes from transcriptomic profiles of matched pairs of in vitro GSC and DGC models. By evaluating the DGC signature using single cell data, we confirmed the presence of cell subpopulations emulated by in vitro culture models within a primary tumor. The DGC signature was correlated with the mesenchymal subtype and a poor prognosis in large GBM cohorts such as The Cancer Genome Atlas and Ivy Glioblastoma Atlas Project. In silico signaling pathway analysis suggested a role of DGCs in macrophage infiltration. Consistent with in silico findings, in vitro DGC models promoted macrophage migration. In vivo, coimplantation of DGCs and GSCs reduced the survival of tumor xenograft-bearing mice and increased macrophage infiltration into tumor tissue compared with transplantation of GSCs alone. DGCs exhibited a significant increase in YAP/TAZ/TEAD activity compared with GSCs. CCN1, a transcriptional target of YAP/TAZ, was selected from the DGC signature as a candidate secreted protein involved in macrophage recruitment. In fact, CCN1 was secreted abundantly from DGCs, but not GSCs. DGCs promoted macrophage migration in vitro and macrophage infiltration into tumor tissue in vivo through secretion of CCN1. Collectively, these results demonstrate that DGCs contribute to GSC-dependent tumor progression by shaping a mesenchymal microenvironment via CCN1-mediated macrophage infiltration. This study provides new insight into the complex GBM microenvironment consisting of heterogeneous cells.
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