Tumour-associated macrophages secrete pleiotrophin to promote PTPRZ1 signalling in glioblastoma stem cells for tumour growth
Yu Shi, Yi Ping, Wenchao Zhou, Zhi Cheng He, Cong Chen, Baishijiao Bian, Lin Zhang, Lu Chen, Xun Lan, Xian Chao Zhang, Kai Zhou, Qing Liu, Hua Long, Ti Wei Fu, Xiao Ning Zhang, Mianfu Cao, Zhi Huang, Xiaoguang Fang, Xiuxing Wang, Hua Feng, Xiao-Hong Yao, Shi‐Cang Yu, You Hong Cui, Xia Zhang, Jeremy N. Rich, Shideng Bao, Xiu Wu Bian
Abstract
Abstract Intense infiltration of tumour-associated macrophages (TAMs) facilitates malignant growth of glioblastoma (GBM), but the underlying mechanisms remain undefined. Herein, we report that TAMs secrete abundant pleiotrophin (PTN) to stimulate glioma stem cells (GSCs) through its receptor PTPRZ1 thus promoting GBM malignant growth through PTN–PTPRZ1 paracrine signalling. PTN expression correlates with infiltration of CD11b+/CD163+ TAMs and poor prognosis of GBM patients. Co-implantation of M2-like macrophages (MLCs) promoted GSC-driven tumour growth, but silencing PTN expression in MLCs mitigated their pro-tumorigenic activity. The PTN receptor PTPRZ1 is preferentially expressed in GSCs and also predicts GBM poor prognosis. Disrupting PTPRZ1 abrogated GSC maintenance and tumorigenic potential. Moreover, blocking the PTN–PTPRZ1 signalling by shRNA or anti-PTPRZ1 antibody potently suppressed GBM tumour growth and prolonged animal survival. Our study uncovered a critical molecular crosstalk between TAMs and GSCs through the PTN–PTPRZ1 paracrine signalling to support GBM malignant growth, indicating that targeting this signalling axis may have therapeutic potential.