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CSF1-ETS2-induced microRNA in myeloid cells promote metastatic tumor growth

Oncogene volume 34, pages 3651–3661 (2015)Cite this article

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Abstract

Metastasis of solid tumors is associated with poor prognosis and bleak survival rates. Tumor-infiltrating myeloid cells (TIMs) are known to promote metastasis, but the mechanisms underlying their collaboration with tumor cells remain unknown. Here, we report an oncogenic role for microRNA (miR) in driving M2 reprogramming in TIMs, characterized by the acquisition of pro-tumor and pro-angiogenic properties. The expression of miR-21, miR-29a, miR-142-3p and miR-223 increased in myeloid cells during tumor progression in mouse models of breast cancer and melanoma metastasis. Further, we show that these miRs are regulated by the CSF1-ETS2 pathway in macrophages. A loss-of-function approach utilizing selective depletion of the miR-processing enzyme Dicer in mature myeloid cells blocks angiogenesis and metastatic tumor growth. Ectopic expression of miR-21 and miR-29a promotes angiogenesis and tumor cell proliferation through the downregulation of anti-angiogenic genes such as Col4a2, Spry1 and Timp3, whereas knockdown of the miRs impedes these processes. miR-21 and miR-29a are expressed in Csf1r+ myeloid cells associated with human metastatic breast cancer, and levels of these miRs in CD115+ non-classical monocytes correlates with metastatic tumor burden in patients. Taken together, our results suggest that miR-21 and miR-29a are essential for the pro-tumor functions of myeloid cells and the CSF1-ETS2 pathway upstream of the miRs serves as an attractive therapeutic target for the inhibition of M2 remodeling of macrophages during malignancy. In addition, miR-21 and miR-29a in circulating myeloid cells may potentially serve as biomarkers to measure therapeutic efficacy of targeted therapies for CSF1 signaling.

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Acknowledgements

We thank Yongqi Wu for help with flow cytometry. We also wish to acknowledge the histology core, OSU Comprehensive Cancer Center Microarray, Nucleic Acids, Analytical Cytometry, Microscopy and Biostatistics Core Shared Resources for technical assistance. This work was funded through National Institutes of Health grants (NIHPO1CA097189 and RO1CA053271) and the Evelyn Simmers Foundation to MCO.

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Authors and Affiliations

  1. Department of Molecular and Cellular Biochemistry, The Ohio State University College of Medicine, Columbus, OH, USA

    H Mathsyaraja, K Thies, D A Taffany & M C Ostrowski

  2. The Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA

    H Mathsyaraja, K Thies, D A Taffany, T Liu, C Shapiro, J Otero, C Timmers, M B Lustberg, J Chalmers, G Leone & M C Ostrowski

  3. Department of Chemical Engineering, The Ohio State University, Columbus, OH, USA

    C Deighan & J Chalmers

  4. Department of Biomedical Informatics, Center for Biostatistics, The Ohio State University, Columbus, OH, USA

    L Yu & S A Fernandez

  5. Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, OH, USA,

    C Shapiro & M B Lustberg

  6. Department of Pathology, Ohio State University College of Medicine, Columbus, OH, USA

    J Otero

  7. Department of Molecular Virology, Immunology & Medical Genetics, The Ohio State University College of Medicine, Columbus, OH, USA

    G Leone

  8. Department of Molecular Genetics, The Ohio State University, Columbus, OH, USA

    G Leone

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Mathsyaraja, H., Thies, K., Taffany, D. et al. CSF1-ETS2-induced microRNA in myeloid cells promote metastatic tumor growth. Oncogene 34, 3651–3661 (2015). https://doi.org/10.1038/onc.2014.294

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