Lung mesenchymal cells elicit lipid storage in neutrophils that fuel breast cancer lung metastasis.

Document Type

Article

Publication Date

11-2020

Keywords

JMG

JAX Source

Nat Immunol 2020 Nov; 21(11):1444-1455

Volume

21

Issue

11

First Page

1444

Last Page

1455

ISSN

1529-2916

PMID

32958928

DOI

https://doi.org/10.1038/s41590-020-0783-5CA1

Grant

CA188093,CA23707,CA034196,The Jackson Laboratory Director's Innovation Fund

Abstract

Acquisition of a lipid-laden phenotype by immune cells has been defined in infectious diseases and atherosclerosis but remains largely uncharacterized in cancer. Here, in breast cancer models, we found that neutrophils are induced to accumulate neutral lipids upon interaction with resident mesenchymal cells in the premetastatic lung. Lung mesenchymal cells elicit this process through repressing the adipose triglyceride lipase (ATGL) activity in neutrophils in prostaglandin E2-dependent and -independent manners. In vivo, neutrophil-specific deletion of genes encoding ATGL or ATGL inhibitory factors altered neutrophil lipid profiles and breast tumor lung metastasis in mice. Mechanistically, lipids stored in lung neutrophils are transported to metastatic tumor cells through a macropinocytosis-lysosome pathway, endowing tumor cells with augmented survival and proliferative capacities. Pharmacological inhibition of macropinocytosis significantly reduced metastatic colonization by breast tumor cells in vivo. Collectively, our work reveals that neutrophils serve as an energy reservoir to fuel breast cancer lung metastasis.

Comments

We acknowledge critical comments from E. T. Liu, N. A. Rosenthal, K. Seburn and C. Robinett. We also thank G. Stafford for RNA-seq analysis and W. Schott for cell sorting, as well as The Jackson Laboratory Scientific Service for assistance.

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