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 language | American English |
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Pages (from-to) | 3902-3915.e6 |
Journal | Cell Reports |
Volume | 27 |
Issue number | 13 |
DOIs | |
State | Published - 25 Jun 2019 |
Bibliographical note
Funding Information:We acknowledge the Goodman Cancer Research Centre histology core facility, the Cell Vision Core Facility, and the Metabolomics Facility for their support with analyses and training. We thank Cynthia Lavoie for technical support and Dr. Josie Ursini-Siegel and members of the Siegel laboratory for their thoughtful discussions and critical reading of the manuscript. This work was supported by an operating grant to P.M.S. from the Cancer Research Society . B.E.H. acknowledges support from the Charlotte and Leo Karassik Foundation PhD Fellowship and the Rolande and Marcel Gosselin Graduate Studentship . P.M.S. is a McGill University William Dawson Scholar .
Funding Information:
We acknowledge the Goodman Cancer Research Centre histology core facility, the Cell Vision Core Facility, and the Metabolomics Facility for their support with analyses and training. We thank Cynthia Lavoie for technical support and Dr. Josie Ursini-Siegel and members of the Siegel laboratory for their thoughtful discussions and critical reading of the manuscript. This work was supported by an operating grant to P.M.S. from the Cancer Research Society. B.E.H. acknowledges support from the Charlotte and Leo Karassik Foundation PhD Fellowship and the Rolande and Marcel Gosselin Graduate Studentship. P.M.S. is a McGill University William Dawson Scholar. Conceptualization, B.E.H. S.T. and P.M.S.; Methodology, B.E.H. S.T. R.M.J. S.A. C.L. J.S. M.G.A. E.H.M. J.S.-P. and P.M.S.; Validation, B.E.H. S.T. R.M.J. M.G.A. S.A. C.L. J.S. and E.H.M.; Formal Analysis, B.E.H. S.T. R.M.J. S.A. C.L. E.H.M. J.S. R.F. L.R. and P.M.S.; Investigation, B.E.H. S.T. S.A. C.L. M.G.A. E.H.M. J.S. S.V. L.R. and Z.G.; Resources, B.E.H. S.T. S.A. C.L. J.S. M.G.A. E.H.M. S.V. L.R. A.M. I.R.W. Z.G. R.G.J. J.S.-P. and P.M.S.; Data Curation, B.E.H. S.T. S.A. C.L. M.G.A. E.H.M. J.S. S.V. and L.R.; Writing-Original Draft, B.E.H. and P.M.S.; Writing- Review & Editing, B.E.H. and P.M.S.; Visualization, B.E.H. R.M.J. S.A. C.L. J.S. E.H.M. and P.M.S.; Supervision, S.T. and P.M.S.; Project Administration, P.M.S.; Funding Acquisition, P.M.S. The authors declare no competing interests.
Publisher Copyright:
© 2019 The Authors
Keywords
- NETosis
- metabolic flexibility
- metastasis
- neutrophil plasticity