Obesity is characterized by chronic systemic inflammation and enhances cancer metastasis and mortality. Obesity promotes breast cancer metastasis to lung in a neutrophil-dependent manner; however, the upstream regulatory mechanisms of this process remain unknown. Here, we show that obesity-induced monocytes underlie neutrophil activation and breast cancer lung metastasis. Using mass cytometry, obesity favors the expansion of myeloid lineages while restricting lymphoid cells within the peripheral blood. RNA sequencing and flow cytometry revealed that obesity-associated monocytes resemble professional antigen-presenting cells due to a shift in their development and exhibit enhanced MHCII expression and CXCL2 production. Monocyte induction of the CXCL2–CXCR2 axis underlies neutrophil activation and release of neutrophil extracellular traps to promote metastasis, and enhancement of this signaling axis is observed in lung metastases from obese cancer patients. Our findings provide mechanistic insight into the relationship between obesity and cancer by broadening our understanding of the interactive role that myeloid cells play in this process.
Obesity alters monocyte developmental trajectories to enhance metastasis
Disclosures: P.O. Fiset reported consulting fees and honoraria from Amgen, BMS, Merck, AstraZeneca, Pfizer, Astellas, Incyte, EMD Serono, and Hoffmann La Roche outside the submitted work. J.D. Spicer reported consulting fees and honoraria from Roche, Merck, AstraZeneca, BMS, Novartis, Chemocentryx, Amgen, Protalix Biotherapeutics, Xenetic Biosciences, and Regeneron and grants to the institution from Roche, Merck, AstraZeneca, BMS, Protalix Biotherapeutics, and CLS Therapeutics. No other disclosures were reported.
Sheri A.C. McDowell, Simon Milette, Samuel Doré, Miranda W. Yu, Mark Sorin, Liam Wilson, Lysanne Desharnais, Alyssa Cristea, Ozgun Varol, Aline Atallah, Anikka Swaby, Valérie Breton, Azadeh Arabzadeh, Sarah Petrecca, Hamza Loucif, Aanya Bhagrath, Meghan De Meo, Katherine D. Lach, Marianne S.M. Issac, Benoit Fiset, Roni F. Rayes, Judith N. Mandl, Jörg H. Fritz, Pierre O. Fiset, Peter R. Holt, Andrew J. Dannenberg, Jonathan D. Spicer, Logan A. Walsh, Daniela F. Quail; Obesity alters monocyte developmental trajectories to enhance metastasis. J Exp Med 7 August 2023; 220 (8): e20220509. doi: https://doi.org/10.1084/jem.20220509
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