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

doi:10.1016/j.celrep.2019.05.091

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

Department of Developmental Biology and Cancer Research

Research output: Contribution to journal › Article › peer-review

110 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 language	American English
Pages (from-to)	3902-3915.e6
Journal	Cell Reports
Volume	27
Issue number	13
DOIs	https://doi.org/10.1016/j.celrep.2019.05.091
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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.celrep.2019.05.091

Cite this

Hsu, B. E., Tabariès, S., Johnson, R. M., Andrzejewski, S., Senecal, J., Lehuédé, C., Annis, M. G., Ma, E. H., Völs, S., Ramsay, L. A., Froment, R., Monast, A., Watson, I. R., Granot, Z., Jones, R. G., St-Pierre, J., & Siegel, P. M. (2019). Immature Low-Density Neutrophils Exhibit Metabolic Flexibility that Facilitates Breast Cancer Liver Metastasis. Cell Reports, 27(13), 3902-3915.e6. https://doi.org/10.1016/j.celrep.2019.05.091

@article{1b28802f88ae47a39a625c03a2eaa724,

title = "Immature Low-Density Neutrophils Exhibit Metabolic Flexibility that Facilitates Breast Cancer Liver Metastasis",

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.",

keywords = "NETosis, metabolic flexibility, metastasis, neutrophil plasticity",

author = "Hsu, {Brian E.} and S{\'e}bastien Tabari{\`e}s and Johnson, {Radia M.} and Sylvia Andrzejewski and Julien Senecal and Camille Lehu{\'e}d{\'e} and Annis, {Matthew G.} and Ma, {Eric H.} and Sandra V{\"o}ls and Ramsay, {Lee Ann} and Remi Froment and Anie Monast and Watson, {Ian R.} and Zvi Granot and Jones, {Russell G.} and Julie St-Pierre and Siegel, {Peter M.}",

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: {\textcopyright} 2019 The Authors",

year = "2019",

month = jun,

day = "25",

doi = "10.1016/j.celrep.2019.05.091",

language = "American English",

volume = "27",

pages = "3902--3915.e6",

journal = "Cell Reports",

issn = "2211-1247",

publisher = "Cell Press",

number = "13",

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Hsu, BE, Tabariès, S, Johnson, RM, Andrzejewski, S, Senecal, J, Lehuédé, C, Annis, MG, Ma, EH, Völs, S, Ramsay, LA, Froment, R, Monast, A, Watson, IR, Granot, Z, Jones, RG, St-Pierre, J & Siegel, PM 2019, 'Immature Low-Density Neutrophils Exhibit Metabolic Flexibility that Facilitates Breast Cancer Liver Metastasis', Cell Reports, vol. 27, no. 13, pp. 3902-3915.e6. https://doi.org/10.1016/j.celrep.2019.05.091

TY - JOUR

T1 - Immature Low-Density Neutrophils Exhibit Metabolic Flexibility that Facilitates Breast Cancer Liver Metastasis

AU - Hsu, Brian E.

AU - Tabariès, Sébastien

AU - Johnson, Radia M.

AU - Andrzejewski, Sylvia

AU - Senecal, Julien

AU - Lehuédé, Camille

AU - Annis, Matthew G.

AU - Ma, Eric H.

AU - Völs, Sandra

AU - Ramsay, Lee Ann

AU - Froment, Remi

AU - Monast, Anie

AU - Watson, Ian R.

AU - Granot, Zvi

AU - Jones, Russell G.

AU - St-Pierre, Julie

AU - Siegel, Peter M.

N1 - 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

PY - 2019/6/25

Y1 - 2019/6/25

N2 - 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.

AB - 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.

KW - NETosis

KW - metabolic flexibility

KW - metastasis

KW - neutrophil plasticity

UR - http://www.scopus.com/inward/record.url?scp=85067181483&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2019.05.091

DO - 10.1016/j.celrep.2019.05.091

M3 - Article

C2 - 31242422

AN - SCOPUS:85067181483

SN - 2211-1247

VL - 27

SP - 3902-3915.e6

JO - Cell Reports

JF - Cell Reports

IS - 13

ER -

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

Abstract

Bibliographical note

Keywords

UN SDGs

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