CCDC25: precise navigator for neutrophil extracellular traps on the prometastatic road
Ruochen Liu, Erhu Zhao, Feng Wang, Hongjuan Cui
Abstract
The dissemination of cancer cells called metastasis accounts for the majority of deaths of cancer patients. Neutrophil extracellular traps (NETs) released by neutrophils to fight pathogens have been shown to promote metastasis in mouse models. However, the mechanism behind how NETs boost metastasis remains elusive. In a recent study in Nature, 1 Yang et al reported that NETs are abundant in the liver metastases of patients with breast and colon cancers, and that the risk of liver metastasis in patients with early-stage breast cancer can be predicted by monitoring the levels of serum NETs. Furthermore, Yang et al. 1 elucidated that the DNA component of NETs (NET-DNA) acts as a chemotactic factor that is recognized by coiled-coil domain containing protein 25 (CCDC25), a cytoplasmic membrane-localized extracellular DNA sensor of cancer cells, which in turn activates the integrin-linked kinase (ILK)–β-parvin–RAC1–CDC42 cascade to promote metastasis (Fig. 1 ). The clinical importance of CCDC25 was confirmed by Yang et al., 1 and targeting CCDC25 inhibits NET-mediated metastasis in mouse models, suggesting a potential therapeutic strategy to halt the metastasis. Fig. 1 The alternative text for this image may have been generated using AI. Full size image NET-DNA recognized by the plasma membrane protein CCDC25 promotes cancer metastasis. Neutrophil at distant tissue (liver) extrude NETs. The DNA sensor CCDC25 on the surface of cancer cells binds to the NET-DNA and subsequently activating the ILK–β-parvin–RAC1–CDC42 cascade, which induce cytoskeleton remodeling, migration, adhesion and proliferation of the cancer cells