Journal
NATURE
Volume 522, Issue 7556, Pages 349-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nature14407
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Funding
- Fonds Wetenschappelijk Onderzoek (FWO)
- Fondazione Umberto Veronesi
- Wellcome Trust
- European Research Council
- Medical Research Council [G0802255] Funding Source: researchfish
- National Institute for Health Research [ACF-2006-04-005] Funding Source: researchfish
- MRC [G0802255] Funding Source: UKRI
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Mutations or amplification of the MET proto-oncogene are involved in the pathogenesis of several tumours(1-4), which rely on the constitutive engagement of this pathway for their growth and survival(1,5). However, MET is expressed not only by cancer cells but also by tumour-associated stromal cells, although its precise role in this compartment is not well characterized(6-11). Here we show that MET is required for neutrophil chemoattraction and cytotoxicity in response to its ligand hepatocyte growth factor (HGF). Met deletion in mouse neutrophils enhances tumour growth and metastasis. This phenotype correlates with reduced neutrophil infiltration to both the primary tumour and metastatic sites. Similarly, Met is necessary for neutrophil transudation during colitis, skin rash or peritonitis. Mechanistically, Met is induced by tumour-derived tumour necrosis factor (TNF)-alpha or other inflammatory stimuli in both mouse and human neutrophils. This induction is instrumental for neutrophil transmigration across an activated endothelium and for inducible nitric oxide synthase production upon HGF stimulation. Consequently, HGF/MET-dependent nitric oxide release by neutrophils promotes cancer cell killing, which abates tumour growth and metastasis. After systemic administration of a MET kinase inhibitor, we prove that the therapeutic benefit of MET targeting in cancer cells is partly countered by the pro-tumoural effect arising from MET blockade in neutrophils. Our work identifies an unprecedented role of MET in neutrophils, suggests a potential 'Achilles' heel' of MET-targeted therapies in cancer, and supports the rationale for evaluating anti-MET drugs in certain inflammatory diseases.
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