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Melanoma cell metastasis via P-selectin-mediated activation of acid sphingomyelinase in platelets

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Abstract

Metastatic dissemination of cancer cells is one of the hallmarks of malignancy and accounts for approximately 90 % of human cancer deaths. Within the blood vasculature, tumor cells may aggregate with platelets to form clots, adhere to and spread onto endothelial cells, and finally extravasate to form metastatic colonies. We have previously shown that sphingolipids play a central role in the interaction of tumor cells with platelets; this interaction is a prerequisite for hematogenous tumor metastasis in at least some tumor models. Here we show that the interaction between melanoma cells and platelets results in rapid and transient activation and secretion of acid sphingomyelinase (Asm) in WT but not in P-selectin-deficient platelets. Stimulation of P-selectin resulted in activation of p38 MAPK, and inhibition of p38 MAPK in platelets prevented the secretion of Asm after interaction with tumor cells. Intravenous injection of melanoma cells into WT mice resulted in multiple lung metastases, while in P-selectin-deficient mice pulmonary tumor metastasis and trapping of tumor cells in the lung was significantly reduced. Pre-incubation of tumor cells with recombinant ASM restored trapping of B16F10 melanoma cells in the lung in P-selectin-deficient mice. These findings indicate a novel pathway in tumor metastasis, i.e., tumor cell mediated activation of P-selectin in platelets, followed by activation and secretion of Asm and in turn release of ceramide and tumor metastasis. The data suggest that p38 MAPK acts downstream from P-selectin and is necessary for the secretion of Asm.

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Acknowledgments

We thank F. Witte, S. Moyrer and S. Harde for excellent help with the manuscript, artwork and animal experiments. This study was supported by DFG Grant Gu 335/24-1 to Erich Gulbins.

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    Authors and Affiliations

    1. Department of Molecular Biology, University Hospital Essen, University of Duisburg-Essen, Hufelandstrasse 55, 45122, Essen, Germany

      Katrin Anne Becker, Nadine Beckmann, Constantin Adams, Gabriele Hessler, Melanie Kramer, Erich Gulbins & Alexander Carpinteiro

    2. Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, OH, 45267-0558, USA

      Erich Gulbins

    3. Clinic for Hematology, University Hospital Essen, University of Duisburg-Essen, Hufelandstrasse 55, 45122, Essen, Germany

      Alexander Carpinteiro

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    1. Katrin Anne Becker
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    Correspondence to Alexander Carpinteiro.

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    All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

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    Katrin Anne Becker and Nadine Beckmann have contributed equally to this work.

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    Becker, K.A., Beckmann, N., Adams, C. et al. Melanoma cell metastasis via P-selectin-mediated activation of acid sphingomyelinase in platelets. Clin Exp Metastasis 34, 25–35 (2017). https://doi.org/10.1007/s10585-016-9826-6

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