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The soluble glycoprotein NMB (GPNMB) produced by macrophages induces cancer stemness and metastasis via CD44 and IL-33


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.

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Supervising, researching and designing the study and writing the manuscript: C.B., P.A.; performing in vitro experiments and acquiring data: C.B., M.L., E.D., A.V., F.S.C., V.R., N.P., E.E., M.T., F.M.F.; performing phosphoproteomic assays and protein profiling: E.M.B., S.M., A.C.; performing in vivo experiment and acquiring data: C.B., R.A., E.D., M.L.; performing immunohistochemistry experiments: E.D., M.L.; performing gene expression analysis: L.M., I.C., S.M.; analyzing and interpreting data (e.g., statistical analysis, figures): E.D., C.B.

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Correspondence to P. Allavena or C. Belgiovine.

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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).

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  • cancer stem cells
  • IL-33
  • metastasis
  • tumor associated macrophages

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