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

Cancer patients who have undergone successful treatment can experience relapse of their disease years or even decades later. This is because cancer cells that have disseminated beyond the primary tumor site enter a state of dormancy, where they remain viable but not proliferating. Eventually, by mechanisms that are poorly understood, these clinically undetectable cells “wake up” and form actively growing metastases. Studying mouse models, Albrengues et al. found that sustained lung inflammation and the accompanying formation of neutrophil extracellular traps (NETs) could convert dormant cancer cells to aggressive lung metastases (see the Perspective by Aguirre-Ghiso). Awakening of these cells was associated with NET-mediated remodeling of the extracellular matrix and could be prevented by an antibody against the remodeled version of a matrix protein called laminin-111.Science, this issue p. eaao4227; see also p. 1314 INTRODUCTION : Most cancer patients die from cancer that recurs after spreading to a different tissue, rather than from their original tumor. After successful treatment of the original tumor, cancer cells that have disseminated to other sites can undergo dormancy, remaining viable but not proliferating. In breast, prostate, and other cancers, cancer cells can remain dormant and clinically undetectable for years and even decades before recurring, or awakening, as metastatic cancer. Little is known about what might initiate cancer awakening, and this in turn reduces our opportunities to prevent metastasis. RATIONALE : Epidemiological studies have suggested that inflammation is linked to a higher risk of breast cancer recurrence after a period of clinical dormancy. Smoking, which causes chronic lung inflammation, is also associated with a higher risk of recurrence. However, whether inflammation can cause awakening is not clear. Inflammatory cells, such as neutrophils, can provide many different signals that promote cancer progression. Neutrophils can kill harmful microorganisms by the release of neutrophil extracellular traps (NETs) into the extracellular space. NETs are scaffolds of DNA with associated cytotoxic proteins and proteases [e.g., neutrophil elastase (NE) and matrix metalloproteinase 9 (MMP9)]. NETs induced by bacteria or by cancer cells can promote metastasis, but the mechanism by which this occurs is not known. In this study, we tested whether NETs formed during lung inflammation could induce awakening. RESULTS : We found that sustained experimental lung inflammation—induced by either tobacco smoke exposure or nasal instillation of lipopolysaccharide (LPS)—converted dormant cancer cells to aggressive lung metastases in mice. Both types of sustained inflammation also caused the formation of NETs. Inhibiting NET formation or digesting the NETs’ DNA scaffold prevented conversion of single disseminated cancer cells to growing metastases in mouse models of breast and prostate cancer. The NET DNA bound to the extracellular matrix (ECM) protein laminin, thus bringing two NET-associated proteases, NE and MMP9, to their substrate. This in turn facilitated a sequential cleavage of laminin, first by NE and then by MMP9. The NET-mediated proteolytic remodeling of laminin revealed an epitope that triggered proliferation of dormant cancer cells through integrin activation and FAK/ERK/MLCK/YAP signaling. We generated a blocking antibody against NET-remodeled laminin, and this antibody prevented or reduced tobacco smoke exposure– or LPS-induced inflammation from awakening dormant cancer cells in mice. CONCLUSION : Our data implicate NETs and NET-mediated ECM remodeling as critical mediators of inflammation-induced awakening in mouse models of dormancy. We propose that NETs awaken cancer by concentrating neutrophil proteases at the ECM protein laminin, allowing for sequential proteolytic remodeling of laminin and leading to integrin-mediated signaling in the cancer cells. Our findings set the stage for epidemiological studies to test possible links among inflammation or smoking, NETs, and recurrence after dorman y in human patients. If such links can be established, we envision that approaches similar to the ones used in mouse models in our study could be used to target NETs and their downstream effectors to reduce the risk of cancer recurrence in human patients. NETs formed during lung inflammation awaken dormant cancer cells.Lung inflammation—caused, for instance, by tobacco smoke exposure—leads to NET formation. Two proteases on the NETs sequentially cleave the extracellular matrix protein laminin. This cleavage generates an epitope that activates integrin signaling and proliferation of the previously dormant cancer cells. Antibodies blocking the NET-generated laminin epitope prevent inflammation-induced awakening.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 α3β1 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.

Science 2018

Voir le bulletin