Open AccessLung mesenchymal cells elicit lipid storage in neutrophils that fuel breast cancer lung metastasis
Author(s) -
Peishan Li,
Mingyang Lu,
Jiayuan Shi,
Zheng Gong,
Hua Li,
Qing Li,
Bora Lim,
Xiang H.-F. Zhang,
Xiaowen Chen,
Sheng Li,
Leonard D. Shultz,
Guosheng Ren
Publication year - 2020
Publication title -
nature immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 9.074
H-Index - 388
eISSN - 1529-2916
pISSN - 1529-2908
DOI - 10.1038/s41590-020-0783-5
Subject(s) - metastasis , cancer research , mesenchymal stem cell , immune system , biology , lipid droplet , breast cancer , pinocytosis , cancer , immunology , medicine , microbiology and biotechnology , cell , genetics , endocytosis
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.