DMBT1-liver metastasis

The liver is a major target organ for breast cancer metastasis, while the regulatory mechanism of liver colonization of breast cancer remains largely unclear. Neutrophils are known to play important roles in metastatic colonization of cancer cells by formation of neutrophil extracellular traps (NETs). Here we show the role and mechanism of a subpopulation of Kupffer cells (KCs), the liver resident macrophages, in mediating tumoral induction of NETs and liver metastasis. NETs are activated more abundantly in liver metastases of breast cancer, as compared to metastases to other organs and primary tumors. Liver-tropic tumor cells induce CD62L-expressing KCs by a secretory protein DMBT1, and CD62L+ KCs activate neutrophils for NETosis via the chemokine CCL8. Inhibition of CCL8 or its receptor on neutrophils, CCR1, impairs NETosis and metastasis. In addition, we identified a KC membrane protein MUC1 that binds to DMBT1 and subsequently activates NFκB signaling of KCs, leading to CCL8 and CD62L expression. KC targeting with MUC1 inhibition effectively suppresses liver metastasis. Furthermore, a DMBT1 neutralizing antibody was developed with promise to inhibit tumor-KC interaction and treat metastatic cancer. In conclusion, our work reveals a KC subset that accounts for the liver tropism of breast cancer cells and NETs, and provides potential strategies in metastasis treatment.