In cancer, myeloid cells have tumor-supporting roles. We reported that the protein GPNMB (glycoprotein nonmetastatic B) was profoundly upregulated in macrophages interacting with tumor cells. Here, using mouse tumor models, we show that macrophage-derived soluble GPNMB increases tumor growth and metastasis in Gpnmb-mutant mice (DBA/2J). GPNMB triggers in the cancer cells the formation of self-renewing spheroids, which are characterized by the expression of cancer stem cell markers, prolonged cell survival and increased tumor-forming ability. Through the CD44 receptor, GPNMB mechanistically activates tumor cells to express the cytokine IL-33 and its receptor IL-1R1L. We also determined that recombinant IL-33 binding to IL-1R1L is sufficient to induce tumor spheroid formation with features of cancer stem cells. Overall, our results reveal a new paracrine axis, GPNMB and IL-33, which is activated during the cross talk of macrophages with tumor cells and eventually promotes cancer cell survival, the expansion of cancer stem cells and the acquisition of a metastatic phenotype.
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This work was supported by IG grants from the Italian Association for Cancer Research (AIRC) to P.A. and grants from the Italian Ministry of Health (GR-2013-02356521) to E.M.B. In addition, E.D. is a recipient of a fellowship from AIRC. We thank Fabio Pasqualini for his help in immunohistochemistry experiments and Marina Sironi and Roberta Migliore for their contributions to the in vivo experiments.
The authors declare no competing interests.
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Liguori, M., Digifico, E., Vacchini, A. et al. The soluble glycoprotein NMB (GPNMB) produced by macrophages induces cancer stemness and metastasis via CD44 and IL-33. Cell Mol Immunol 18, 711–722 (2021). https://doi.org/10.1038/s41423-020-0501-0
- cancer stem cells
- tumor associated macrophages
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