@article{3711e9c5c32347a2a04dc5e14f8bddc7,
title = "Neutrophil oxidative stress mediates obesity-associated vascular dysfunction and metastatic transmigration",
abstract = "Metastasis is the leading cause of cancer-related deaths, and obesity is associated with increased breast cancer (BC) metastasis. Preclinical studies have shown that obese adipose tissue induces lung neutrophilia associated with enhanced BC metastasis to this site. Here we show that obesity leads to neutrophil-dependent impairment of vascular integrity through loss of endothelial adhesions, enabling cancer cell extravasation into the lung. Mechanistically, neutrophil-produced reactive oxygen species in obese mice increase neutrophil extracellular DNA traps (NETs) and weaken endothelial junctions, facilitating the influx of tumor cells from the peripheral circulation. In vivo treatment with catalase, NET inhibitors or genetic deletion of Nos2 reversed this effect in preclinical models of obesity. Imaging mass cytometry of lung metastasis samples from patients with cancer revealed an enrichment in neutrophils with low catalase levels correlating with elevated body mass index. Our data provide insights into potentially targetable mechanisms that underlie the progression of BC in the obese population.",
author = "McDowell, {Sheri A.C.} and Luo, {Robin B.E.} and Azadeh Arabzadeh and Samuel Dor{\'e} and Bennett, {Nicolas C.} and Val{\'e}rie Breton and Elham Karimi and Morteza Rezanejad and Yang, {Ryan R.} and Lach, {Katherine D.} and Issac, {Marianne S.M.} and Bozena Samborska and Perus, {Lucas J.M.} and Dan Moldoveanu and Yuhong Wei and Benoit Fiset and Rayes, {Roni F.} and Watson, {Ian R.} and Lawrence Kazak and Guiot, {Marie Christine} and Fiset, {Pierre O.} and Spicer, {Jonathan D.} and Dannenberg, {Andrew J.} and Walsh, {Logan A.} and Quail, {Daniela F.}",
note = "Funding Information: P.O.F. has received honoraria and consultancy fees from Amgen Canada, AstraZeneca Canada, Bristol Myers Squibb, EMD Serono, Hoffmann-La Roche, Merck Canada, Pfizer Canada and Roche Canada. J.D.S. has received consultancy fees for BMS, Merck, Amgen, AstraZeneca, Protalix and TransHit Bio, and grant funding from AstraZeneca, CLS Therapeutics, Merck and Hoffman La Roche. All other authors declare no competing interests. Funding Information: We thank the Goodman Cancer Research Centre and Life Sciences Complex at McGill University for core facility support, including the Single Cell and Imaging Mass Cytometry Platform (SCIMAP, Y.W.), Histology facility (Cleber Moraes), the Comparative Medicine and Animal Resource Centre and the Flow Cytometry facility. SCIMAP is supported by a McGill MI4 Platform grant and the Fraser Memorial Trust. This study was funded by the Susan G. Komen Foundation (D.F.Q., grant no. CCR18548032), Canada Foundation for Innovation (D.F.Q., JELF-37488; L.A.W., JELF-39178), Canadian Institutes of Health Research (D.F.Q., PJT-159742; L.A.W., PJT-162137) and the Breast Cancer Research Foundation (A.J.D., BCRF-19-034). D.F.Q. is supported by a Tier II Canada Research Chair in Tumor Microenvironment Research. L.A.W. is supported by a Rosalind and Morris Goodman Chair in Lung Cancer Research. S.A.C.M is supported by a Charlotte and Leo Karassik Foundation Fellowship, a Canada Graduate Scholarship from the Canadian Institutes of Health Research and a Canderel Graduate Studentship Award from the Goodman Cancer Research Centre. Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.",
year = "2021",
month = may,
doi = "10.1038/s43018-021-00194-9",
language = "English (US)",
volume = "2",
pages = "545--562",
journal = "Nature Cancer",
issn = "2662-1347",
publisher = "Nature Research",
number = "5",
}