Abstract
Pre-metastatic niche formation is critical for the colonization of disseminated cancer cells in distant organs. Here we find that lung mesenchymal stromal cells (LMSCs) at pre-metastatic stage possess potent metastasis-promoting activity. RNA-seq reveals an upregulation of complement 3 (C3) in those LMSCs. C3 is found to promote neutrophil recruitment and the formation of neutrophil extracellular traps (NETs), which facilitate cancer cell metastasis to the lungs. C3 expression in LMSCs is induced and sustained by Th2 cytokines in a STAT6-dependent manner. LMSCs-driven lung metastasis is abolished in Th1-skewing Stat6-deficient mice. Blockade of IL-4 by antibody also attenuates LMSCs-driven cancer metastasis to the lungs. Consistently, metastasis is greatly enhanced in Th2-skewing T-bet-deficient mice or in nude mice adoptively transferred with T-bet-deficient T cells. Increased C3 levels are also detected in breast cancer patients. Our results suggest that targeting the Th2-STAT6-C3-NETs cascade may reduce breast cancer metastasis to the lungs.
Highlights
Pre-metastatic niche formation is critical for the colonization of disseminated cancer cells in distant organs
We set out to study the components of pulmonary PM niche and their respective roles in metastasis using the lung metastatic Mouse mammary tumor virus (MMTV)-polyoma middle T antigen (PyMT) mammary tumor mouse model[30,31]
We found that Pad[4] and myeloperxodase (Mpo), which are associated with NETs42, were all upregulated in neutrophils treated with PM-lung mesenchymal stromal cells (LMSCs) in comparison to those treated with A-LMSCs (Supplementary Fig. 4C)
Summary
Pre-metastatic niche formation is critical for the colonization of disseminated cancer cells in distant organs. RNA-seq reveals an upregulation of complement 3 (C3) in those LMSCs. C3 is found to promote neutrophil recruitment and the formation of neutrophil extracellular traps (NETs), which facilitate cancer cell metastasis to the lungs. Tumor-derived growth factors[10], inflammatory cytokines[11], chemokines[12], and exosomes[13,14] are known to be critical for the initiation and evolution of PM niche. We demonstrate that resident MSCs are critically involved in the formation of pulmonary PM niche of breast cancer cells. This study reveals how local MSCs respond to inflammatory cytokines and how they prepare the PM niche for the colonization of cancer cells in the lungs
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