Tumor cell-secreted soluble uPAR functions as a neutrophil chemoattractant to promote triple-negative breast cancer metastasis

Abstract

Abstract Accumulating evidence have demonstrated that circulating tumor cell (CTC) clusters have higher metastatic ability than single CTCs, and correlates with worse cancer patient’s outcomes. The heterotypic CTC clusters such as neutrophil-CTC clusters recently were identified in both cancer mouse models and cancer patients, leading to more efficient metastasis formation compared with homotypic CTC clusters. However, the mechanism by which neutrophils are associated with CTCs remains elusive. In this study, we found that the intercellular adhesion molecule (ICAM-1) on triple-negative breast cancer (TNBC) cells mediates their binding with CD11b+ neutrophils, and CD11b deficiency inhibited TNBC metastasis In vivo. Additionally, CD11b mediated H2O2 production of neutrophils. Further studies indicated that ICAM-1 promotes uPAR secretion, which functions as a chemoattractant for neutrophils. Knockdown of uPAR in ICAM-1+ TNBC cells reduced lung-infiltrating neutrophils, and lung metastasis. The bioinformatics analysis showed uPAR is highly expressed in TNBCs, which positively correlates with higher neutrophil infiltration and negatively with breast cancer patient’s survival. Together, our findings discover a novel chemoattractant role of suPAR in TNBC metastasis, and provides a rationale for targeting ICAM-1-uPAR-CD11b axis to block CTC-neutrophil cluster formation, and its-mediated metastasis.