Neutrophil extracellular traps sequester circulating tumor cells via 1-integrin mediated interactions

Despite advances in cancer treatment, metastasis remains today the main cause of cancer death. Local control through complete surgical resection of the primary tumor continues to be a key principle in cancer treatment. However, surgical interventions themselves lead to adverse oncologic outcomes and are associated with significantly increased rates of metastasis. Neutrophils through release of neutrophil extracellular traps (NETs) in response to infections were shown to be able to capture circulating cancer cells, and in doing so, support the development of metastatic disease. To be able to intervene on this process, understanding the exact molecular nature of these mechanisms is crucial. We therefore hypothesize and demonstrate that 1-integrin is an important factor mediating the interactions between circulating tumor cells and NETs. We show that 1-integrin expression on both cancer cells and NETs is important for the adhesion of circulating tumor cells to NETs both in vitro and in vivo. Using a murine model of intra-abdominal sepsis to mimic the postoperative inflammatory environment, we show that 1-integrin expression is upregulated in the context of inflammation in vivo. Ultimately, we show that this increased early cancer cell adhesion to NETs in vivo and this effect is abrogated when mice are administered DNAse 1. Our data therefore sheds light on the first molecular mechanism by which NETs can trap circulating tumor cells (CTCs), broadening our understanding of this process. What's new? Surgical removal of tumors can increase inflammation. When neutrophils respond to inflammatory signals, they sometimes form web-like projections called neutrophil extracellular traps (NETs). These NETs are able to enhance metastasis, because they bind circulating tumor cells (CTCs) and cause them to adhere to distant organs. In our study, the authors found that 1-integrins play an essential role in the interaction between NETs and tumor cells. Then, they found that hepatic adhesion of CTCs in mice could be significantly reduced by blocking 1-integrins. These results suggest that targeting 1-integrins may help to reduce metastases.