Nature: Key Targets for Neutrophils To Promote Breast Cancer Metastasis Found - CCDC25

Neutrophils are immune cells that provide the body with the first line of defense against infectionHowever, in many cases, neutrophils also have the ability to promote cell cell metastasisIn a new paper published June 11 in the journal Nature, Professor Song Erwei from Sun Yat-sen Memorial Hospital at Sun Yat-sen University explains how neutrophils help the deadly processA key feature of neutrophils is their ability to squeeze a structure called neutrophil extracellular traps (NEUtrophil extracellular trap, NET) into their surroundingsNET is a mesh structure of DNA covered with toxic enzymes that normally captures and kills invading microorganismsHowever, there is growing evidence that NET mediates the development and enhancement of cancer cell aggression, but how they promote cancer cell metastasis remains largely unknownIn the new study, scientists first evaluated NET in 544 breast cancer patients with primary and metastatic tumorsThe results showed that there were very few NET in primary tumors, but there was a large amount of NET in the liver metastasis ( a common part of breast cancer spread)What's more, the researchers also found that higher levels of NET DNA in the blood of early breast cancer patients were associated with later cancer metastasis to the liverThis suggests that monitoring NET DNA in blood samples may be a way to assess the prognosis of the diseaseTo investigate the relationship between NET and cancer cells, the researchers transplanted human- or mouse-derived breast cancer cells into mice and analyzed metastatic tumor cellsThe results showed that NET accumulated in the liver of both mouse modelsThis finding is consistent with the results of the analysis from the patientFigure 1 Net promotes cancer metastasis in the liver before metastasis (Source: Nature) study reports that in mouse models, NET "appears" there before metastatic cells can be detected in the liverThe study found that the ability of cancer cells to transition to the liver depended on NET, because when NET was removed (through DNA degradation enzyme DNase I, or mice genetically modified to lack the enzyme needed for NET formation), metastasis was greatly impairedAlthough previous studies have suggested that NET-dependent liver metastasis occurs through an indirect mechanism of "NET capture of passing cancer cells," new research reveals that net DNA directly stimulates the migration of human breast cancer cells in in vitro tests
Figure 2 NET-DNA binds to CCDC25 on tumor cells and promotes their distant metastasis (Source: Nature) Study further investigates how this migration is induced By adding a label to NET DNA, the researchers hope to find proteins that interact with them Eventually, they found that a receptor called CCDC25 binds to NET DNA CCDC25 is present on the surface of cancer cells and binds to NET DNA with high specificity and affinity, enabling cancer cells to perceive NET Impressively, the researchers also identified specific extracellular parts of CCDC25 binding to NET DNA Figure 3 The interaction of the transmembrane protein CCDC25 with NET-DNA at the N side (Source: Nature) confirms that NET-mediated cancer cell transport stimulation is driven by CCDC25 Because, when CCDC25 is removed from an in vitro cultured human breast cancer cell or a sample of the patient's primary breast cancer cell, in in vitro testing, the migration of cancer cells is greatly reduced The removal of CCDC25 from the surface of cancer cells in mice significantly reduced the formation of liver metastasis compared to mice where CCDC25 was still present, while also reducing pulmonary metastasis after fat polysaccharides (previously reported that LPS triggers pulmonary metastasis associated with NET) Figure 4 CCDC25 interacts with ILK at its C side and signals through ILK-beta-parvin cascade (Source: Nature) At the end, scientists reveal how tumor cells benefit from the interaction between NET and CCDC25 They found a protein in cancer cells that interacts with CCDC25, an enzyme that regulates the processofs of cell migration and proliferation, integrator-linked kinase, ILK When ILK or its downstream signaling partners are removed, the protein beta-parvin loses function, cancer cells grow and exercise severely impaired in the body, and liver metastases are reduced in mice These results suggest that the combination of NET DNA and CCDC25 enhances aggressive behavior of cancer cells by activating an ILK-mediated signal cascade Another important finding of the study is that NET DNA's ability to promote liver metastasis is not breast cancer-specific NET was also observed in liver tumors in colon cancer patients and in mouse liver tumors in which human colon cancer cells were injected If human breast cancer and colon cancer cells are modified to increase CCDC25 levels, this helps promote liver metastasis in mice injected with these cancer cells In addition, scientists found a correlation between high abundance of CCDC25 in primary tumors and shorter long-term survival in patients with multiple cancer types, suggesting that monitoring the expression of CCDC25 may help predict prognosis Figure 5 A process that promotes the spread of cancer cells (Photo: Nature) Future research needs to assess the feasibility of targeting CCDC25 for cancer treatment Expression of CCDC25 in different types of cells and possible function in normal cells are also to be investigated Since studies have identified the exact extracellular part of CCDC25's interaction with NET DNA, it is possible to develop specific inhibitors to prevent this interaction The new work from Sun Yat-sen Memorial Hospital at Sun Yat-sen University represents a key step forward in curbing the spread of cancer and could lead to a new anti-cancer treatment, according to an op-ed in Nature magazine