Glycoprotein NMB mediates bidirectional GSC-TAM interactions to promote tumor progression
Yang Liu, Lizhi Pang, Fatima Khan, Junyan Wu, Fei Zhou, Craig Horbinski, Shideng Bao, Jennifer S. Yu, Justin D. Lathia, Peiwen Chen
Yang Liu, Lizhi Pang, Fatima Khan, Junyan Wu, Fei Zhou, Craig Horbinski, Shideng Bao, Jennifer S. Yu, Justin D. Lathia, Peiwen Chen
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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

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Figure 2

GPNMB promotes the glycolysis of GSCs.

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GPNMB promotes the glycolysis of GSCs. (A) GSEA analysis of single-cell ...
(A) GSEA analysis of single-cell RNA-Seq (scRNA-Seq) data from human GBM tumors (EGAS00001004871) shows top enriched WikiPathways signatures in tumors with TAMs expressing high GPNMB compared to low GPNMB. (B and C) Extracellular acidification rate (ECAR) of GSC272 cells (B) and CT2A cells (C) treated with GPNMB recombinant protein (100 ng/mL) for 24 hours. ECAR was obtained from the Seahorse experiments, and glucose was added at the indicated time point. n = 3 independent samples. (D and E) ECAR of GSC272 cells treated with the conditioned media (CM) of THP-1 macrophages (D) and HMC3 microglia (E) expressing shRNA control (shC) or GPNMB shRNA (shGPNMB) for 24 hours. ECAR was obtained from the Seahorse experiments, and glucose was added at the indicated time point. n = 6 independent samples. (F–H) Quantification of relative L-lactate levels in GSC272 (F), GSC2 (G), and CT2A cells (H) treated with GPNMB recombinant protein (100 ng/mL) for 24 hours. n = 3 independent samples. Student’s t test. (I and J) Quantification of relative L-lactate levels in GSC272 cells treated with the CM of THP-1 macrophages (I) and HMC3 microglia (J) expressing shC or shGPNMB for 24 hours. n = 3 independent samples. One-way ANOVA test. (K and L) Quantification of relative L-lactate levels in GSC2 cells treated with the CM of THP-1 macrophages (K) and HMC3 microglia (L) expressing shC or shGPNMB for 24 hours. n = 3 independent samples. One-way ANOVA test. (M and N) Quantification of relative L-lactate levels in CT2A cells treated with the CM of Raw264.7 macrophages (M) and SIM-A9 microglia (N) expressing shC or shGpnmb for 24 hours. n = 3 independent samples. One-way ANOVA test. *P < 0.05, **P < 0.01.