Immature Low-Density Neutrophils Exhibit Metabolic Flexibility that Facilitates Breast Cancer Liver Metastasis.
Neutrophils are phenotypically heterogeneous and exert either anti- or pro-metastatic functions. We show that cancer-cell-derived G-CSF is necessary, but not sufficient, to mobilize immature low-density neutrophils (iLDNs) 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. iLDNs 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. We demonstrate that NETosis is an important neutrophil function that promotes breast cancer liver metastasis. iLDNs rely on the catabolism of glutamate and proline to support mitochondrial-dependent metabolism in the absence of glucose, which enables sustained NETosis. These data reveal that distinct pro-metastatic neutrophil populations exhibit a high degree of metabolic flexibility, which facilitates the formation of liver metastases.
['Hsu|Brian E|BE|', 'Tabariès|Sébastien|S|', 'Johnson|Radia M|RM|', 'Andrzejewski|Sylvia|S|', 'Senecal|Julien|J|', 'Lehuédé|Camille|C|', 'Annis|Matthew G|MG|', 'Ma|Eric H|EH|', 'Völs|Sandra|S|', 'Ramsay|LeeAnn|L|', 'Froment|Remi|R|', 'Monast|Anie|A|', 'Watson|Ian R|IR|', 'Granot|Zvi|Z|', 'Jones|Russell G|RG|', 'St-Pierre|Julie|J|', 'Siegel|Peter M|PM|']
D000818:Animals D045744:Cell Line, Tumor D005260:Female D008113:Liver Neoplasms D008325:Mammary Neoplasms, Experimental D051379:Mice D008807:Mice, Inbred BALB C D009362:Neoplasm Metastasis D009504:Neutrophils
metabolic flexibility metastasis NETosis neutrophil plasticity