The PTPRZ1-MET/STAT3/ISG20 axis in glioma stem-like cells modulates tumor-associated macrophage polarization.

Recent studies have revealed that PTPRZ1-MET (ZM) fusion plays a pivotal role in the progression of glioma to glioblastoma multiforme (GBM), thus serving as a biomarker to distinguish between primary GBM and secondary GBM (sGBM). However, the mechanisms through which ZM fusion influences this progression remain to be elucidated. GBMs with ZM showed poorer prognoses and greater infiltration of tumor-associated macrophages (TAMs) than those without ZM. Glioma stem-like cells (GSCs) and TAMs play complex roles in glioma recurrence, glioma progression and therapy resistance. In this study, we analyzed RNA-seq data from sGBM patients' glioma tissues with or without ZM fusion, and found that stemness and macrophage markers were more highly expressed in sGBM patients harboring ZM than in those without ZM fusion. ZM enhanced the self-renewal and proliferation of GSCs, thereby accelerating glioma progression. In addition, ZM-positive GSCs facilitated the infiltration of TAMs and drove their polarization toward an immunosuppressive phenotype, which was primarily accomplished through the extracellular secretion of ISG20. Our research identified the MET–STAT3–ISG20 axis within GSCs, thus demonstrating the critical role of ZM in GBM initiation and progression. Our study demonstrated that, in contrast to ZM-positive differentiated glioma cells, ZM-positive GSCs upregulated ISG20 expression through the MET–STAT3–ISG20 axis. The extracellular secretion of ISG20 recruited and induced M2-like polarization in macrophages, thereby promoting tumor progression. Our results reveal a novel mechanism involved in ZM-positive GBM pathogenesis and identify potential therapeutic targets. Schematic model of the interaction between glioma stem-like cells (GSCs) with PTPRZ1-MET fusion (ZM) and tumor-associated macrophages (TAMs). ZM can induce activation of MET–STAT3–ISG20 axis in GSCs. The overexpressed ISG20 protein is secreted from GSCs with ZM, recruiting TAMs and inducing their M2-like polarization. The M2-like TAMs maintain the stemness of GSCs and promote glioma progression. Inhibiting STAT3 activation in ZM GSCs can block these events. [Display omitted] • Glioma with PTPRZ1-MET (ZM) is rich in glioma stem-like cells (GSCs) and macrophages. • GSCs with ZM (not tumor cells) facilitate immunosuppressive macrophage infiltration. • ZM induces MET – STAT3 – ISG20 axis activation in GSCs, but not in differentiated cells. • ZM induces the overexpression and secretion of ISG20 protein in GSCs. • ISG20-educated macrophages promote glioma progression. [ABSTRACT FROM AUTHOR]