DNA of neutrophil extracellular traps promotes cancer metastasis via CCDC25.
Linbin YangQiang LiuXiaoqian ZhangXinwei LiuBoxuan ZhouJianing ChenDi HuangJiaqian LiHeliang LiFei ChenJiang LiuYue XingXueman ChenShicheng SuErwei SongPublished in: Nature (2020)
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.
Keyphrases
- circulating tumor
- cell free
- poor prognosis
- single molecule
- early stage
- liver metastases
- papillary thyroid
- nucleic acid
- long non coding rna
- gene expression
- lymph node
- chronic kidney disease
- end stage renal disease
- stem cells
- mouse model
- escherichia coli
- induced apoptosis
- binding protein
- single cell
- pseudomonas aeruginosa
- staphylococcus aureus
- lymph node metastasis
- endoplasmic reticulum stress
- biofilm formation
- small molecule
- bone marrow
- candida albicans
- signaling pathway
- sentinel lymph node
- childhood cancer