Immature Low-Density Neutrophils Exhibit Metabolic Flexibility that Facilitates Breast Cancer Liver Metastasis

Cell Rep. 2019 Jun 25;27(13):3902-3915.e6. doi: 10.1016/j.celrep.2019.05.091.


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.

Keywords: NETosis; metabolic flexibility; metastasis; neutrophil plasticity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Female
  • Liver Neoplasms / metabolism*
  • Liver Neoplasms / pathology
  • Liver Neoplasms / secondary
  • Mammary Neoplasms, Experimental / metabolism*
  • Mammary Neoplasms, Experimental / pathology
  • Mice
  • Mice, Inbred BALB C
  • Neoplasm Metastasis
  • Neutrophils / metabolism*
  • Neutrophils / pathology