DNA of neutrophil extracellular traps promotes cancer metastasis via CCDC25

Linbin Yang, Qiang Liu, Xiaoqian Zhang, Xinwei Liu, Boxuan Zhou, Jianing Chen, Di Huang, Jiaqian Li, Heliang Li, Fei Chen, Jiang Liu, Yue Xing, Xueman Chen, Shicheng Su () and Erwei Song ()
Additional contact information
Linbin Yang: Sun Yat-Sen University
Qiang Liu: Sun Yat-Sen University
Xiaoqian Zhang: Sun Yat-Sen University
Xinwei Liu: Sun Yat-Sen University
Boxuan Zhou: Sun Yat-Sen University
Jianing Chen: Sun Yat-Sen University
Di Huang: Sun Yat-Sen University
Jiaqian Li: Sun Yat-Sen University
Heliang Li: Sun Yat-Sen University
Fei Chen: Sun Yat-Sen University
Jiang Liu: Sun Yat-Sen University
Yue Xing: Sun Yat-Sen University
Xueman Chen: Sun Yat-Sen University
Shicheng Su: Sun Yat-Sen University
Erwei Song: Sun Yat-Sen University

Nature, 2020, vol. 583, issue 7814, 133-138

Abstract: Abstract Neutrophil extracellular traps (NETs), which consist of chromatin DNA filaments coated with granule proteins, are released by neutrophils to trap microorganisms1–3. Recent studies have suggested that the DNA component of NETs (NET-DNA) is associated with cancer metastasis in mouse models4–6. However, the functional role and clinical importance of NET-DNA in metastasis in patients with cancer remain unclear. Here we show that NETs are abundant in the liver metastases of patients with breast and colon cancers, and that serum NETs can predict the occurrence of liver metastases in patients with early-stage breast cancer. NET-DNA acts as a chemotactic factor to attract cancer cells, rather than merely acting as a ‘trap’ for them; in several mouse models, NETs in the liver or lungs were found to attract cancer cells to form distant metastases. We identify the transmembrane protein CCDC25 as a NET-DNA receptor on cancer cells that senses extracellular DNA and subsequently activates the ILK–β-parvin pathway to enhance cell motility. NET-mediated metastasis is abrogated in CCDC25-knockout cells. Clinically, we show that the expression of CCDC25 on primary cancer cells is closely associated with a poor prognosis for patients. Overall, we describe a transmembrane DNA receptor that mediates NET-dependent metastasis, and suggest that targeting CCDC25 could be an appealing therapeutic strategy for the prevention of cancer metastasis.

Date: 2020
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DOI: 10.1038/s41586-020-2394-6

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