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

M Liguori, E Digifico, A Vacchini, R Avigni, F S Colombo, E M Borroni, F M Farina, S Milanesi, A Castagna, L Mannarino, I Craparotta, S Marchini, E Erba, N Panini, M Tamborini, V Rimoldi, P Allavena, C Belgiovine

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
JournalCellular and Molecular Immunology
DOIs
Publication statusE-pub ahead of print - Jul 29 2020

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