Two novel alkaline earth zincophosphites, namely CaZn(HPO3)2 and Ba2Zn(HPO3)3, were successfully synthesized using hydrothermal conditions. CaZn(HPO3)2 exhibits a three-dimensional (3D) anionic framework with a 6-connect uni-node topology of pcu α-Po...

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype, and metastasis is the major cause of cancer morbidity and mortality. Therefore, it is urgent to discover novel therapeutic targets and develop effective treatments for this lethal disease. Circulating tumor cells (CTCs) are considered “seeds of metastasis”. Compared to single CTCs, our previous studies have demonstrated that CD44 homophilic interaction mediates CTC aggregation to enhance the stemness, survival and metastatic ability of aggregated cells. Importantly, the presence of CD44+ CTC clusters correlates with a poor prognosis in breast cancer patients. Here, we further investigated the underlying mechanism of how CD44-mediated cell aggregation promotes TNBC metastasis. We found that cell detachment, which mimics the condition when tumor cells detach from the extracellular matrix (ECM) to metastasize, induces lipid raft disruption in single cells, but lipid rafts integrity is maintained in aggregated cells. We further found that lipid rafts integrity in aggregated cells is required for Rac1 activation to prevent anoikis. In addition, CD44 and γ-secretase coexisted at lipid rafts in aggregated cells, which promotes CD44 cleavage and generates CD44 intracellular domain (CD44 ICD) to enhance stemness. Consequently, lipid rafts disruption inhibited Rac1 activation, CD44 ICD generation and metastasis. These data reveal a new mechanism of cell aggregation-mediated TNBC metastasis via maintaining lipid raft integrity after cell detachment. The finding provides a potential therapeutic strategy to prevent CTC cluster-initiated metastasis by disrupting lipid raft integrity and its-mediated downstream pathways.

Accumulating evidence demonstrates that circulating tumor cell (CTC) clusters have higher metastatic ability than single CTCs and negatively correlate with cancer patient outcomes. Along with homotypic CTC clusters, heterotypic CTC clusters (such as neutrophil–CTC clusters), which have been identified in both cancer mouse models and cancer patients, lead to more efficient metastasis formation and worse patient outcomes. However, the mechanism by which neutrophils bind to CTCs remains elusive. In this study, we found that intercellular adhesion molecule-1 (ICAM-1) on triple-negative breast cancer (TNBC) cells and CD11b on neutrophils mediate tumor cell–neutrophil binding. Consequently, CD11b deficiency inhibited tumor cell–neutrophil binding and TNBC metastasis. Furthermore, CD11b mediated hydrogen peroxide (H2O2) production from neutrophils. Moreover, we found that ICAM-1 in TNBC cells promotes tumor cells to secrete suPAR, which functions as a chemoattractant for neutrophils. Knockdown of uPAR in ICAM-1+ TNBC cells reduced lung-infiltrating neutrophils and lung metastasis. Bioinformatics analysis confirmed that uPAR is highly expressed in TNBCs, which positively correlates with higher neutrophil infiltration and negatively correlates with breast cancer patient survival. Collectively, our findings provide new insight into how neutrophils bind to CTC to facilitate metastasis and discover a novel potential therapeutic strategy by blocking the ICAM-1-suPAR-CD11b axis to inhibit TNBC metastasis.