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The platelet NLRP3 inflammasome is upregulated in a murine model of pancreatic cancer and promotes platelet aggregation and tumor growth

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Abstract

Platelets are activated in solid cancers, including pancreatic ductal adenocarcinoma (PDA), a highly aggressive malignancy with a devastating prognosis and limited therapeutic options. The mechanisms by which activated platelets regulate tumor progression are poorly understood. The nucleotide-binding domain leucine-rich repeat containing protein 3 (NLRP3) inflammasome is a key inflammatory mechanism recently identified in platelets, which controls platelet activation and aggregation. In an orthotopic PDA mouse model involving surgical implantation of Panc02 murine cancer cells into the tail of the pancreas, we show that the NLRP3 inflammasome in circulating platelets is upregulated in pancreatic cancer. Pharmacological inhibition or genetic ablation of NLRP3 in platelets resulted in decreased platelet activation, platelet aggregation, and tumor progression. Moreover, interfering with platelet NLRP3 signaling significantly improved survival of tumor-bearing mice. Hence, the platelet NLRP3 inflammasome plays a critical role in PDA and might represent a novel therapeutic target.

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Acknowledgements

The work for this article was performed while Drs. Brian A. Boone, Herbert J. Zeh III, and Sebastian Vogel were at University of Pittsburgh. The opinions expressed in this article are the authors’ own and do not reflect the view of the National Institutes of Health, the Department of Health and Human Services, or the United States government.

Funding

This work was supported by the U.S. National Institutes of Health (R01CA181450 to HJZ and MTL) and the German Research Foundation (DFG) KFO 274 (VO 2126/1-1 to SV and MG) and TRR 240 (374031971 to MG). The Nikon A1 confocal microscope used in this study was purchased with NIH grant 1S10OD019973-01 awarded to investigators at the University of Pittsburgh Center for Biologic Imaging.

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Author notes

  1. Brian A. Boone

    Present address: Department of Surgery, West Virginia University, Morgantown, WV, USA

  2. Herbert J. Zeh III

    Present address: Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA

  3. Sebastian Vogel

    Present address: Department of Perioperative Medicine, Pediatric Anesthesiology and Critical Care Section, National Institutes of Health Clinical Center, NIH, 10 Center Drive, Building 10 Room B1B50, Bethesda, MD, 20814, USA

  4. Brian A. Boone and Pranav Murthy contributed equally to this study as first authors.

Authors and Affiliations

  1. Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA

    Brian A. Boone, Pranav Murthy, Jennifer L. Miller-Ocuin, Xiaoyan Liang, Kira L. Russell, Patricia Loughran, Michael T. Lotze, Herbert J. Zeh III & Sebastian Vogel

  2. Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, PA, USA

    Patricia Loughran

  3. Department of Cardiology and Cardiovascular Diseases, Eberhard Karls University Tübingen, Tübingen, Germany

    Meinrad Gawaz & Sebastian Vogel

  4. Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA

    Michael T. Lotze

  5. Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA

    Michael T. Lotze

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  1. Brian A. Boone
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Correspondence to Sebastian Vogel.

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All procedures performed in studies involving animals were in accordance with the ethical standards of the institution at which the studies were conducted. All applicable international, national, and institutional guidelines for the care and use of animals were followed. This article does not contain any studies with human participants performed by any of the authors.

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Boone, B.A., Murthy, P., Miller-Ocuin, J.L. et al. The platelet NLRP3 inflammasome is upregulated in a murine model of pancreatic cancer and promotes platelet aggregation and tumor growth. Ann Hematol 98, 1603–1610 (2019). https://doi.org/10.1007/s00277-019-03692-0

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