Immature low-density neutrophils exhibit metabolic flexibility that facilitates breast cancer liver metastasis

Neutrophils play a key role in the control of metastatic progression. Neutrophils are phenotypically heterogeneous and can exert either anti- or pro-metastatic functions. Here, we demonstrate that tumor cells capable of forming liver metastases induce an accumulation of neutrophils in the peripheral blood and liver parenchyma. Cancer cell-derived G-CSF, in concert with other factors, mobilizes immature low-density neutrophils that promote liver metastasis. In contrast, mature high-density neutrophils inhibit the formation of liver metastases. Transcriptomic and metabolomic analyses of high- and low- density neutrophils reveal engagement of numerous metabolic pathways specifically in low-density neutrophils. Low-density neutrophils exhibit enhanced global bioenergetic capacity, through their ability to engage mitochondrial-dependent ATP production, and remain capable of executing pro-metastatic neutrophil functions, including NETosis, under nutrient-deprived conditions. Together, these data reveal that distinct pro-metastatic neutrophil populations exhibit a high degree of metabolic flexibility, which facilitates metastatic progression and the formation of liver metastases. 4 samples of Naïve neutrophils (bone marrow), 4 samples HDNs (from peripheral blood of liver metastasis bearing mice), 4 samples LDNs (from peripheral blood of liver metastasis bearing mice)