Neutrophil oxidative stress mediates obesity-associated vascular dysfunction and metastatic transmigration

Sheri A.C. McDowell, Robin B.E. Luo, Azadeh Arabzadeh, Samuel Doré, Nicolas C. Bennett, Valérie Breton, Elham Karimi, Morteza Rezanejad, Ryan R. Yang, Katherine D. Lach, Marianne S.M. Issac, Bozena Samborska, Lucas J.M. Perus, Dan Moldoveanu, Yuhong Wei, Benoit Fiset, Roni F. Rayes, Ian R. Watson, Lawrence Kazak, Marie Christine GuiotPierre O. Fiset, Jonathan D. Spicer, Andrew J. Dannenberg, Logan A. Walsh, Daniela F. Quail

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)545-562
Number of pages18
JournalNature Cancer
Volume2
Issue number5
DOIs
StatePublished - May 2021

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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