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

Brian E. Hsu, Sébastien Tabariès, Radia M. Johnson, Sylvia Andrzejewski, Julien Senecal, Camille Lehuédé, Matthew G. Annis, Eric H. Ma, Sandra Völs, Lee Ann Ramsay, Remi Froment, Anie Monast, Ian R. Watson, Zvi Granot, Russell G. Jones, Julie St-Pierre, Peter M. Siegel*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

130 Scopus citations

Abstract

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 et al. demonstrate that tumor-derived G-CSF, in concert with additional factors, mobilizes immature low-density neutrophils (iLDNs) that promote breast cancer liver metastasis. iLDNs are able to perform pro-metastatic functions under metabolically challenging conditions, such as low glucose, due to their enhanced global bioenergetic capacity.

Original languageAmerican English
Pages (from-to)3902-3915.e6
JournalCell Reports
Volume27
Issue number13
DOIs
StatePublished - 25 Jun 2019

Bibliographical note

Publisher Copyright:
© 2019 The Authors

Keywords

  • NETosis
  • metabolic flexibility
  • metastasis
  • neutrophil plasticity

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