Neutrophil extracellular traps produced during inflammation awaken dormant cancer cells in mice

Jean Albrengues, Mario A. Shields, David Ng, Chun Gwon Park, Alexandra Ambrico, Morgan E. Poindexter, Priya Upadhyay, Dale L. Uyeminami, Arnaud Pommier, Victoria Küttner, Emilis Bružas, Laura Maiorino, Carmelita Bautista, Ellese M. Carmona, Phyllis A. Gimotty, Douglas T. Fearon, Kenneth Chang, Scott K. Lyons, Kent E Pinkerton, Lloyd C. TrotmanMichael S. Goldberg, Johannes T.H. Yeh, Mikala Egeblad

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141 Scopus citations

Abstract

Cancer cells from a primary tumor can disseminate to other tissues, remaining dormant and clinically undetectable for many years. Little is known about the cues that cause these dormant cells to awaken, resume proliferating, and develop into metastases. Studying mouse models, we found that sustained lung inflammation caused by tobacco smoke exposure or nasal instillation of lipopolysaccharide converted disseminated, dormant cancer cells to aggressively growing metastases. Sustained inflammation induced the formation of neutrophil extracellular traps (NETs), and these were required for awakening dormant cancer. Mechanistic analysis revealed that two NET-associated proteases, neutrophil elastase and matrix metalloproteinase 9, sequentially cleaved laminin. The proteolytically remodeled laminin induced proliferation of dormant cancer cells by activating integrin a3b1 signaling. Antibodies against NET-remodeled laminin prevented awakening of dormant cells. Therapies aimed at preventing dormant cell awakening could potentially prolong the survival of cancer patients.

Original languageEnglish (US)
Article numbereaao4227
JournalScience
Volume361
Issue number6409
DOIs
StatePublished - Sep 28 2018

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    Albrengues, J., Shields, M. A., Ng, D., Park, C. G., Ambrico, A., Poindexter, M. E., Upadhyay, P., Uyeminami, D. L., Pommier, A., Küttner, V., Bružas, E., Maiorino, L., Bautista, C., Carmona, E. M., Gimotty, P. A., Fearon, D. T., Chang, K., Lyons, S. K., Pinkerton, K. E., ... Egeblad, M. (2018). Neutrophil extracellular traps produced during inflammation awaken dormant cancer cells in mice. Science, 361(6409), [eaao4227]. https://doi.org/10.1126/science.aao4227