Obesity alters monocyte developmental trajectories to enhance metastasis

Abstract

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.

NETosis: Sculpting tumor metastasis and immunotherapy

“…Obesity is beneficial to expand myeloid lineages, but limiting lymphoid cells in the circulating system. In addition, obesity‐evoked monocytes are the basis of activation of neutrophils and pulmonary metastases of breast carcinoma, resembling professional antigen‐presenting cells because of a transformation during the development and up‐regulated MHCII and CXCL2 101 . Monocytes induced by the CXCL2‐CXCR2 signaling underlie the activation of neutrophils and generation of NETs, thus triggering metastases (Figure 3).…”

Obesity, bone marrow adiposity, and leukemia: Time to act

“…81,144 Obesity-induced increase in the myeloid cell expansion is obvious in the peripheral circulation. 145 The increased BM-A whitening or adiposity in mice with HFD-induced obesity increases the surge in the Ly6C high monocytes (neutrophillike) and neutrophils that precede the ATM rise. [145][146][147] These invasive Ly6C high monocytes have altered immunometabolic reprogramming such as they show high glycolysis and reduced OXPHOS and increased mitochondrial fission.…”

“…145 The increased BM-A whitening or adiposity in mice with HFD-induced obesity increases the surge in the Ly6C high monocytes (neutrophillike) and neutrophils that precede the ATM rise. [145][146][147] These invasive Ly6C high monocytes have altered immunometabolic reprogramming such as they show high glycolysis and reduced OXPHOS and increased mitochondrial fission. Therefore, Ly6C high monocytes developed in the BM of patients with obesity are highly invasive and move to distant ATs to give rise to pro-inflammatory ATMs.…”

“…81 Also, obesity-associated circulating monocytes resemble professional antigen-presenting cells (APCs) due to a shift in their development and overexpression of MHC-II molecules and CXCL2 production. 145 Monocyte induction of the CXCL2-CXCR2 axis underlies neutrophil activation and neutrophil extracellular trap (NET)0 formation and release that is critical for cancer escape and spread. 145 Thus, these pro-inflammatory macrophages may induce "smoldering inflammation" sufficient for developing cancer later in life.…”

Linking Adiposity to Interstitial Lung Disease: The Role of the Dysfunctional Adipocyte and Inflammation

“…How adiposity impacts the profile of these monocytes in ILD and their effects on monocyte-derived macrophage function remains to be clarified. Suggesting a potential interaction, in leptin-deficient (ob/ob) and diet-induced obesity models of obesity, there is evidence of increased circulating monocytes, particularly the inflammatory monocyte subsets and lung tissue monocytes [ 76 ]. A similar blood monocytosis has also been observed in humans with obesity [ 77 ].…”