Advanced Search
Submit Manuscript Volume 31, No 10, Oct 2021
ISSN: 1001-0602
EISSN: 1748-7838 2018
impact factor 17.848*
(Clarivate Analytics, 2019)
Volume 31 Issue 10, October 2021: 1072-1087 |
Pericytes augment glioblastoma cell resistance to temozolomide through CCL5-CCR5 paracrine signaling
Xiao-Ning Zhang1 , Kai-Di Yang1 , Cong Chen1 , Zhi-Cheng He1 , Qiang-Hu Wang2 , Hua Feng3 , Sheng-Qing Lv4 , Yan Wang1 , Min Mao1 , Qing Liu1 , Yao-Yao Tan1 , Wen-Ying Wang1 , Tian-Ran Li1 , Lin-Rong Che5 , Zhong-Yi Qin1,5 , Ling-Xiang Wu2 , Min Luo1 , Chun-Hua Luo1 , Yu-Qi Liu1 , Wen Yin1 , Chao Wang1 , Hai-Tao Guo1 , Qing-Rui Li1 , Bin Wang1,5 , Wei Chen6 , Shuang Wang7 , Yu Shi1,* , Xiu-Wu Bian1,* , Yi-Fang Ping1,*
1Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University) and Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, ChinaGlioblastoma (GBM) is a prevalent and highly lethal form of glioma, with rapid tumor progression and frequent recurrence. Excessive outgrowth of pericytes in GBM governs the ecology of the perivascular niche, but their function in mediating chemoresistance has not been fully explored. Herein, we uncovered that pericytes potentiate DNA damage repair (DDR) in GBM cells residing in the perivascular niche, which induces temozolomide (TMZ) chemoresistance. We found that increased pericyte proportion correlates with accelerated tumor recurrence and worse prognosis. Genetic depletion of pericytes in GBM xenografts enhances TMZ-induced cytotoxicity and prolongs survival of tumor-bearing mice. Mechanistically, C-C motif chemokine ligand 5 (CCL5) secreted by pericytes activates C-C motif chemokine receptor 5 (CCR5) on GBM cells to enable DNA-dependent protein kinase catalytic subunit (DNA-PKcs)-mediated DDR upon TMZ treatment. Disrupting CCL5-CCR5 paracrine signaling through the brain-penetrable CCR5 antagonist maraviroc (MVC) potently inhibits pericyte-promoted DDR and effectively improves the chemotherapeutic efficacy of TMZ. GBM patient-derived xenografts with high CCL5 expression benefit from combined treatment with TMZ and MVC. Our study reveals the role of pericytes as an extrinsic stimulator potentiating DDR signaling in GBM cells and suggests that targeting CCL5-CCR5 signaling could be an effective therapeutic strategy to improve chemotherapeutic efficacy against GBM.
https://doi.org/10.1038/s41422-021-00528-3