Metastatic growth instructed by neutrophil-derived transferrin
Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels la transferrine dérivée des polynucléaires neutrophiles favorise le processus métastatique
The current study uncovers a mechanistic link between neutrophils and cancer metastasis. Transferrin, an iron-transporting protein, is expressed at mRNA and protein levels in mouse and human neutrophils and is mainly responsible for neutrophil-secreted mitogenic activity on tumor cells. GM-CSF, a cytokine largely produced by tumor cells in the metastatic microenvironment, selectively acts on neutrophils to enhance transferrin gene expression, through activation of the Jak/Stat5β pathway. Accordingly, deletion of the transferrin receptor (Tfr1) in tumor cells, blockade of GM-CSF, or inhibition of Jak kinases inhibited mouse tumor lung metastasis. Our findings raise the possibility that inhibiting GM-CSF or the Jak/Stat5b pathway may benefit patients with metastatic diseases and high local neutrophil infiltration. The tumor-promoting functions of neutrophils have been mainly attributed to induction of tumor angiogenesis or suppression of anticancer immunity. However, a direct impact of neutrophils on tumor cell growth and metastasis remains largely uncharacterized. Here, we coupled a proteomic approach with a functional screen to interrogate the secretome of tumor-associated neutrophils. Surprisingly, the iron-transporting protein transferrin was identified as the major mitogen for tumor cells secreted by neutrophils. Depletion of neutrophils inhibited lung metastasis and transferrin production in the metastatic microenvironment. Deletion of transferrin receptor suppressed growth of lung-colonizing tumor cells. Also, media conditioned by neutrophils isolated from metastatic breast cancer patients stimulated growth of human breast cancer cells, an effect that was largely abolished by transferrin immunodepletion. We identified GM-CSF, which is produced primarily by tumor cells, as a selective inducer of de novo transferrin synthesis in neutrophils through the Jak/Stat5β pathway. GM-CSF neutralization or inhibition of Jak kinases curtailed neutrophil transferrin expression in vitro and in vivo as well as cancer metastasis. Thus, transferrin provides a mechanistic link between neutrophils and metastatic growth owing to the ability of tumor-infiltrating neutrophils to locally deliver this growth-promoting protein in response to GM-CSF stimulation. Our study identifies neutrophil-derived transferrin as a key regulator of metastatic tumor cell growth and a therapeutic target for antimetastatic treatment.