Abstracts are provided in the language submitted.

Obesity is linked to greater cancer incidence and death across multiple tumor types, including breast cancer. due, in part, to inflammatory perturbations within adipose tissue that can disrupt homeostasis locally and systemically. We have previously shown that obesity enhances breast cancer metastasis to lung using preclinical models of obesity. This effect was dependent on obesity-associated lung neutrophilia, and was evident as early as 48-hours post-tail vein injection of breast cancer cells, suggesting that obesity influences extravasation. Thus, this study examines how obesity-associated inflammation affects breast cancer extravasation to lung. We show that obesity enhances cancer cell extravasation in association with increased vascular permeability, through loss of endothelial adhesions. This is dependent on neutrophils, such that neutrophil depletion strengthens endothelial integrity and reduces extravasation. Mechanistically, neutrophil-produced reactive oxygen species (ROS) in obese mice increase neutrophil extracellular traps (NETs) and weaken endothelial junctions, facilitating tumor cell extravasation. In vivo treatment with catalase (a ROS scavenger), or NET inhibitors, reverses this effect. Confirming the translational relevance of our findings, we performed imaging mass cytometry on lung metastasis patient samples and observed greater neutrophils with low catalase levels correlating with elevated body mass index. Given that obesity is increasing on a global scale, understanding the mechanistic relationship between obesity and cancer is crucial.

Sheri McDowell