Inflammation-induced neutrophil extracellular traps (NET) awaken dormant cells to promote metastasis.
Major finding: Inflammation-induced neutrophil extracellular traps (NET) awaken dormant cells to promote metastasis.
Mechanism: NETs act as laminin-cleaving protease scaffolds to enable proteolytic remodeling and integrin activation.
Impact: Inflammation may trigger metastatic disease via NETs, suggesting their potential as therapeutic targets.
Cancer cells disseminated from the primary tumor can remain dormant at distant tissue sites for years before developing into metastatic cancer. However, the mechanisms by which dormant disseminated tumor cells resume proliferation remain unclear. Smoking-induced chronic lung inflammation has been linked to an increased risk of lung metastasis, suggesting a potential role for neutrophils, which mediate inflammation and have been linked to cancer cell awaking in experimental models. Neutrophils can kill microorganisms through the formation of neutrophil extracellular traps (NET), which are DNA scaffolds with associated cytotoxic enzymes and proteases that are released into the extracellular space. Albrengues and colleagues sought to determine whether NETs facilitate metastasis after dormancy. In mouse models of tumor dormancy, inflammation induced by lipopolysaccharide (LPS) or tobacco smoke exposure was sufficient to trigger aggressive lung metastases that were associated with NET formation. Blocking NET formation or digesting the NET DNA scaffold suppressed the conversion of disseminated cancer cells to active metastases, indicating that NET formation during inflammation promotes the awakening of dormant cancer cells. Mechanistically, the NET DNA acted as a proteolysis scaffold, binding to the extracellular matrix component laminin and facilitating laminin cleavage by the NET-associated proteases neutrophil elastase and matrix metalloproteinase 9. This laminin remodeling triggered α3β1 integrin activation and downstream FAK/ERK/MLCK/YAP signaling to promote the proliferation of dormant tumor cells. Consistent with these findings, antibody-mediated blockade of NET-remodeled laminin prevented LPS or smoke-induced inflammation from converting dormant cancer cells to metastases in vivo. In addition to elucidating a mechanism by which inflammation promotes NET-mediated laminin remodeling to awaken dormant cancer cells, these findings suggest the potential for therapeutic targeting of NETs to prevent metastasis in patients with dormant cancer.
Albrengues J, Shields MA, Ng D, Park CG, Ambrico A, Poindexter ME, et al. Neutrophil extracellular traps produced during inflammation awaken dormant cancer cells in mice. Science 2018;361:eaao4227.
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