title: MET is required for the recruitment of anti-tumoural neutrophils.
abstract: Mutations or amplification of the MET proto-oncogene are involved in the pathogenesis of several tumours, which rely on the constitutive engagement of this pathway for their growth and survival. 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. 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)-α 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.
authors.affiliation: 1] Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, VIB, Leuven B3000, Belgium [2] Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, Department of Oncology, KU Leuven, Leuven B3000, Belgium.
authors.forename: Veronica
authors.initials: V
authors.lastname: Finisguerra
authors.affiliation: 1] Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, VIB, Leuven B3000, Belgium [2] Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, Department of Oncology, KU Leuven, Leuven B3000, Belgium.
authors.forename: Giusy
authors.initials: G
authors.lastname: Di Conza
authors.affiliation: 1] Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, VIB, Leuven B3000, Belgium [2] Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, Department of Oncology, KU Leuven, Leuven B3000, Belgium.
authors.forename: Mario
authors.initials: M
authors.lastname: Di Matteo
authors.affiliation: 1] Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, VIB, Leuven B3000, Belgium [2] Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, Department of Oncology, KU Leuven, Leuven B3000, Belgium.
authors.forename: Jens
authors.initials: J
authors.lastname: Serneels
authors.affiliation: 1] Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, VIB, Leuven B3000, Belgium [2] Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, Department of Oncology, KU Leuven, Leuven B3000, Belgium [3] Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, 4710-057 Braga, Portugal [4] ICVS/3B's - PT Government Associate Laboratory, 4710-057 Braga/Guimarães, Portugal.
authors.forename: Sandra
authors.initials: S
authors.lastname: Costa
authors.affiliation: Department of Infection and Immunity, University of Sheffield, Sheffield S10 2RX, UK.
authors.forename: A A Roger
authors.initials: AA
authors.lastname: Thompson
authors.affiliation: 1] Respiratory Division, University Hospital Gasthuisberg, Leuven B3000, Belgium [2] Laboratory of Translational Genetics, Vesalius Research Center, VIB, Leuven B3000, Belgium [3] Laboratory of Translational Genetics, Vesalius Research Center, Department of Oncology, KU Leuven, Leuven B3000, Belgium.
authors.forename: Els
authors.initials: E
authors.lastname: Wauters
authors.affiliation: Department of Infection and Immunity, University of Sheffield, Sheffield S10 2RX, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Walmsley
authors.affiliation: Digestive Oncology Unit, University Hospital Gasthuisberg, Department of Oncology, KU Leuven, Leuven B3000, Belgium.
authors.forename: Hans
authors.initials: H
authors.lastname: Prenen
authors.affiliation: Department of Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada, The Hebrew University, Jerusalem 91120, Israel.
authors.forename: Zvi
authors.initials: Z
authors.lastname: Granot
authors.affiliation: 1] Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, VIB, Leuven B3000, Belgium [2] Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, Department of Oncology, KU Leuven, Leuven B3000, Belgium.
authors.forename: Andrea
authors.initials: A
authors.lastname: Casazza
authors.affiliation: 1] Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, VIB, Leuven B3000, Belgium [2] Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, Department of Oncology, KU Leuven, Leuven B3000, Belgium.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Mazzone
mesh_terms: D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000494:pharmacology*; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D017353:Gene Deletion; D017228:Hepatocyte Growth Factor; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D000090063:Proto-Oncogene Mas; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012995:Solubility; D057705:Transendothelial and Transepithelial Migration; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met