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

Acta Neuropathologica Communications

Atsunori Kamiya¹  Atsushi Fujimura²  Keigo Makino³  Yusuke Tomita³  Shuichiro Hirano³  Joji Ishida³  Yosuke Shimazu³  Kentaro Fujii³  Yuji Matsumoto³  Yasuhiko Hattori³  Yoshihiro Otani³  Nobushige Tsuboi³  Isao Date³  Atsuhito Uneda⁴  Kazuhiko Kurozumi⁵ 

[1] Department of Cellular Physiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, 700-8558, Okayama, Japan;Department of Cellular Physiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, 700-8558, Okayama, Japan;Neutron Therapy Research Center, Okayama University, 2-5-1 Shikata-cho, Kita-ku, 700-8558, Okayama, Japan;Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, 700-8558, Okayama, Japan;Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, 700-8558, Okayama, Japan;Department of Cellular Physiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, 700-8558, Okayama, Japan;Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, 700-8558, Okayama, Japan;Department of Neurosurgery, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, 431-3139, Hamamatsu, Shizuoka, Japan;

关键词: Differentiated glioblastoma cell;    Glioblastoma stem cell;    CCN1;    YAP/TAZ;    TEAD;    Mesenchymal subtype;    Macrophage;    Microenvironment;    Glioma;    Glioblastoma;   

DOI  :  10.1186/s40478-021-01124-7

来源: Springer

【 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.

【 授权许可】

CC BY