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 4

GPNMB promotes GSC glycolysis and stemness by activating PYK2/RSK2 axis.

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GPNMB promotes GSC glycolysis and stemness by activating PYK2/RSK2 axis....
(A and B) Representative images (A) and quantification (B) of human phospho-kinases in GSC2 cells treated with or without GPNMB recombinant protein (100 ng/mL) for 1 hour. Affected kinases are indicated. (C and D) Immunoblots for P-RSK2, RSK2, P-PYK2, and PYK2 in lysates of GSC272 cells treated with GPNMB recombinant protein at the indicated concentrations and time points. (E) Extracellular acidification rate (ECAR) of GSC272 cells treated with GPNMB recombinant protein (100 ng/mL) in the presence or absence of PYK2 inhibitor PF-271 (15 nM) or RSK1/2 inhibitor SL0101 (100 μM) for 24 hours. n = 6 independent samples. (F) Relative L-lactate levels in GSC272 cells treated with GPNMB recombinant protein (100 ng/mL) in the presence or absence of PF-271 (15 nM) or SL0101 (100 μM) for 24 hours. n = 3 independent samples. One-way ANOVA test. (G) ECAR of CT2A cells treated with GPNMB recombinant protein (100 ng/mL) in the presence or absence of PF-271 (15 nM) or SL0101 (100 μM) for 24 hours. n = 6 independent samples. (H) Relative L-lactate levels in CT2A cells treated with GPNMB recombinant protein (100 ng/mL) in the presence or absence of PF-271 (15 nM) or SL0101 (100 μM) for 24 hours. n = 3 independent samples. One-way ANOVA test. (I and J) Immunoblots for CD133 and SOX2 in lysates of GSC272 cells treated with GPNMB recombinant protein (100 ng/mL) in the presence or absence of PF-271 (15 nM, I) or SL0101 (100 μM, J) for 24 hours. (K–N) Tumorsphere formation assays of GSC272 cells treated with GPNMB recombinant protein (100 ng/mL) in the presence or absence of PF-271 (15 nM, K and L) or SL0101 (100 μM, M and N) for 2 weeks. Scale bar: 200 μm. n = 3–5 independent samples. One-way ANOVA test. **P < 0.01, ***P < 0.001, n.s., not significant (P > 0.05).