Abstract
Lung mesenchymal cells promoted neutrophil lipid storage; lipids were transferred to tumor cells.
Major Finding: Lung mesenchymal cells promoted neutrophil lipid storage; lipids were transferred to tumor cells.
Concept: Lipid uptake by metastatic tumor cells occurred via macropinocytosis and promoted proliferation.
Impact: This reveals a previously unknown role for neutrophils in metabolic regulation of metastasis.
Neutrophils have been shown to promote the metastasis of solid tumors via immunologic modulation of the premetastatic niche; however, their potential metabolic contributions to metastasis have not been well characterized. Li, Lu, and colleagues found that, in mouse breast cancer models, lung neutrophils exhibited a phenotype distinct from that of bone marrow– or peripheral blood–derived neutrophils prior to lung metastasis. Specifically, lung neutrophils had marked lipid accumulation characterized by upregulation of lipid-storage genes, increased abundance of lipid droplets (which are the primary intracellular storage sites for neutral lipids such as triglycerides), higher levels of triglycerides, and upregulation of inhibitors of the triglyceride-degrading enzyme adipose triglyceride lipase (ATGL). In ex vivo co-culture experiments, only CD140a+ mesenchymal cells (among lung stromal cells) could trigger neutrophils to accumulate lipids and upregulate expression of ATGL inhibitors. These lung-resident mesenchymal cells drove lipid buildup in neutrophils via direct cell–cell contact and secretion of soluble factors, most notably the eicosanoid PGE2, which interacted with the receptor EP2 on neutrophils. Secretion of PGE2 by lung mesenchymal cells was induced by secretion of the inflammatory cytokine IL1β by neutrophils, creating a positive-feedback loop to promote lipid storage by neutrophils. Supporting the mechanism identified via the prior results, Atgl knockout in mouse breast cancer models enhanced lung neutrophil lipid storage and increased lung metastasis. To transfer lipids to metastatic tumor cells, neutrophils released lipid-filled vesicles, which were taken up by tumor cells via macropinocytosis, a form of bulk nonspecific endocytosis, and pharmacologic inhibition of micropinocytosis (but not clathrin- or caveola-dependent endocytosis) prevented lipid transfer from neutrophils to tumor cells. In vitro and in vivo, exposure to lung neutrophil–derived lipids conferred enhanced proliferative capabilities to tumor cells; further, in vivo, lipids from neutrophils promoted metastasis of breast tumors to the lungs. Collectively, these results provide evidence of a role for neutrophils in metabolic regulation of metastasis and supply a mechanism explaining this phenomenon.
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