Glycoprotein NMB mediates bidirectional GSC-TAM interactions to promote tumor progression
Yang Liu, … , Justin D. Lathia, Peiwen Chen
Yang Liu, … , Justin D. Lathia, Peiwen Chen
Published July 8, 2025
Citation Information: JCI Insight. 2025;10(13):e187684. https://doi.org/10.1172/jci.insight.187684.
View: Text | PDF
Research Article Immunology Oncology

Glycoprotein NMB mediates bidirectional GSC-TAM interactions to promote tumor progression

Abstract

Glioblastoma (GBM) is a lethal brain tumor containing a subpopulation of GBM stem cells (GSCs) that interaction with surrounding cells, including infiltrating tumor-associated macrophages and microglia (TAMs). While GSCs and TAMs are in close proximity and likely interact to coordinate tumor growth, a limited number of mechanisms have been identified that support their communication. Here, we identified glycoprotein NMB (GPNMB) as a key factor mediating a unique bidirectional interaction between GSCs and TAMs in GBM. Specifically, GSCs educated macrophages and microglia to preferentially express GPNMB in the GBM tumor microenvironment. As a result, TAM-secreted GPNMB interacted with its receptor CD44 on GSCs to promote their glycolytic and self-renewal abilities via activating the PYK2/RSK2 signaling axis. Disrupting GPNMB-mediated GSC-TAM interplay suppressed tumor progression and self-renewal in GBM mouse models. Our study found a protumor function of GPNMB-mediated GSC-TAM bidirectional communication and supports GPNMB as a promising therapeutic target for GBM.

Authors

Yang Liu, Lizhi Pang, Fatima Khan, Junyan Wu, Fei Zhou, Craig Horbinski, Shideng Bao, Jennifer S. Yu, Justin D. Lathia, Peiwen Chen

×

Figure 1

GSCs upregulate GPNMB expression in TAMs.

Options: View larger image (or click on image) Download as PowerPoint
GSCs upregulate GPNMB expression in TAMs. (A) Strategy for identificatio...
(A) Strategy for identification of the overlapped genes that were upregulated in both GBM-associated microglia and bone marrow–derived macrophage (BMDMs) compared with normal monocytes. The analysis was based on RNA-Seq data (GSE86573) from GBM-associated microglia/BMDMs isolated from the GL261 tumor model and RCAS tumor model and normal microglia and monocytes. (B) The expression pattern of genes in CD45– GBM cells and tumor-associated immune cells (e.g., BMDMs, microglia, neutrophils, CD4+ T cells, and CD8+ T cells) isolated from human GBM tumors based on the Brain TIME dataset (34). (C) Coimmunofluorescence staining for GPNMB (red) and F4/80 (macrophage marker, green) or CX3CR1 (microglia marker, green) in CT2A tumors implanted in C57BL/6 mice. Scale bar: 50 μm. (D–G) Flow cytometry analysis of GPNMB expression in CD11b+CD45hiCD68+ macrophages (D and E) isolated from bone marrow and CD11b+CD45loCX3CR1+ microglia (F and G) isolated from brain tissues of tumor-free C57BL/6 mice and CT2A and QPP7 tumor-bearing C57BL/6 mice. n = 3–6 independent samples. One-way ANOVA test. (H–K) Flow cytometry analysis of GPNMB expression in CD11b+CD45hiCD11c+ DCs, CD11b+CD45loCX3CR1+ microglia (Total MG), CD11b+CD45loCX3CR1+CD206+ microglia (CD206+ MG), CD11b+CD45loCX3CR1+CD206– microglia (CD206– MG), CD11b+CD45hiCD68+ macrophages (Total MΦ), CD11b+CD45hiCD68+CD206+ macrophages (CD206+ MΦ), CD11b+CD45hiCD68+CD206– macrophages (CD206– MΦ), CD11b+CD68+Ly6GloLy6Chi monocytic immature myeloid cells (M-IMCs), and CD11b+CD68+Ly6GhiLy6Clo polymorphonuclear immature myeloid cells (PMN-IMCs) isolated from QPP7 tumors (H and I) and CT2A tumors (J and K) implanted in C57BL/6 mice. n = 3 independent samples. One-way ANOVA test. (L) Immunoblots for GPNMB in lysates of Raw264.7 macrophages and SIM-A9 microglia treated with the conditioned media (CM) of QPP7 GSCs for 24 hours. (M) Immunoblots for GPNMB in lysates of THP-1 macrophage and HMC3 microglia treated with the CM of GSC272 cells for 24 hours. **P < 0.01, ***P < 0.001.