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Tumour-processed osteopontin and lactadherin drive the protumorigenic reprogramming of microglia and glioma progression

Oncogene volume 35, pages 6366–6377 (2016)Cite this article

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Abstract

Tumour tissue is infiltrated by myeloid cells that are reprogrammed into alternatively activated/regenerative (M2) macrophages. The contribution of major signalling pathways and their modulators/targets involved in the macrophage reprogramming is poorly known. Glioblastoma (malignant brain tumour) attracts and reprograms brain-resident microglia and peripheral macrophages into cells that increase invasion, angiogenesis and suppress antitumour immunity. Using a ‘function-first’ approach and glioma secretome proteomics we identified osteopontin and lactadherin as proteins that cooperatively activate amoeboid transformation, phagocytosis and motility of primary microglia cultures via integrins and FAK-Akt (focal adhesion kinase-Akt) signalling. A synthetic peptide interfering with integrin ligands blocks glioma–microglia communication, functional activation and M2 gene expression. We found that osteopontin/secreted phosphoprotein 1 (Spp1) produced by non-transformed cells acts as a proinflammatory factor inducing inflammatory signalling and M1 genes, and counteracts the action of lactadherin. Using constructs encoding functional mutants of osteopontin, we demonstrated sequential processing of Spp1 by thrombin and matrix metalloproteinase-3 and/or -7 (MMP-3 and/or -7) in glioma cells, which generates a microglia-activating form devoid of the inflammatory activity, while retaining the M2 reprogramming potential. A similar form of osteopontin is secreted by human glioma cells but not normal human astrocytes. Knockdown of osteopontin or lactadherin in glioma cells reduces intracranial glioma growth, blocks amoeboid transformation of myeloid cells and affects M2 reprogramming of microglia/macrophages. Our findings demonstrate how glioma cells misuse macrophage-activating signals and redesign primarily proinflammatory signals towards their advantage to induce M2 reprogramming of tumour-infiltrating brain macrophages.

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Acknowledgements

We thank Beata Kaza and Marcin Sliwa for technical assistance. This work was supported by the Grant 2012/04/A/NZ3/00630 (to BK) from the National Science Center (Poland). PG was supported by GA no. 264173 Bio-Imagine and IP2011013171 from the Ministry of Science and Higher Education.

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  1. A Ellert-Miklaszewska, P Wisniewski and M Kijewska: These authors contributed equally to this work.

Authors and Affiliations

  1. Laboratory of Molecular Neurobiology, Neurobiology Center, The Nencki Institute of Experimental Biology, Warsaw, Poland

    A Ellert-Miklaszewska, P Wisniewski, M Kijewska, P Gajdanowicz, D Pszczolkowska, P Przanowski, M Dabrowski, M Maleszewska & B Kaminska

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  1. A Ellert-Miklaszewska
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Correspondence to B Kaminska.

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Ellert-Miklaszewska, A., Wisniewski, P., Kijewska, M. et al. Tumour-processed osteopontin and lactadherin drive the protumorigenic reprogramming of microglia and glioma progression. Oncogene 35, 6366–6377 (2016). https://doi.org/10.1038/onc.2016.55

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