title: The E3 ligase Cbl-b and TAM receptors regulate cancer metastasis via natural killer cells.
abstract: Tumour metastasis is the primary cause of mortality in cancer patients and remains the key challenge for cancer therapy. New therapeutic approaches to block inhibitory pathways of the immune system have renewed hopes for the utility of such therapies. Here we show that genetic deletion of the E3 ubiquitin ligase Cbl-b (casitas B-lineage lymphoma-b) or targeted inactivation of its E3 ligase activity licenses natural killer (NK) cells to spontaneously reject metastatic tumours. The TAM tyrosine kinase receptors Tyro3, Axl and Mer (also known as Mertk) were identified as ubiquitylation substrates for Cbl-b. Treatment of wild-type NK cells with a newly developed small molecule TAM kinase inhibitor conferred therapeutic potential, efficiently enhancing anti-metastatic NK cell activity in vivo. Oral or intraperitoneal administration using this TAM inhibitor markedly reduced murine mammary cancer and melanoma metastases dependent on NK cells. We further report that the anticoagulant warfarin exerts anti-metastatic activity in mice via Cbl-b/TAM receptors in NK cells, providing a molecular explanation for a 50-year-old puzzle in cancer biology. This novel TAM/Cbl-b inhibitory pathway shows that it might be possible to develop a 'pill' that awakens the innate immune system to kill cancer metastases.
authors.affiliation: IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, 1030 Vienna, Austria.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Paolino
authors.affiliation: Lead Discovery Center GmbH, D-44227 Dortmund, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Choidas
authors.affiliation: Medical University Innsbruck, 6020 Innsbruck, Austria.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Wallner
authors.affiliation: IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, 1030 Vienna, Austria.
authors.forename: Blanka
authors.initials: B
authors.lastname: Pranjic
authors.affiliation: IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, 1030 Vienna, Austria.
authors.forename: Iris
authors.initials: I
authors.lastname: Uribesalgo
authors.affiliation: IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, 1030 Vienna, Austria.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Loeser
authors.affiliation: Department of Microbiology and Immunology, Brown University, Providence, Rhode Island 02912, USA.
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Jamieson
authors.affiliation: School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, Western Australia 6009, Perth, Australia.
authors.forename: Wallace Y
authors.initials: WY
authors.lastname: Langdon
authors.affiliation: IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, 1030 Vienna, Austria.
authors.forename: Fumiyo
authors.initials: F
authors.lastname: Ikeda
authors.affiliation: IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, 1030 Vienna, Austria.
authors.forename: Juan Pablo
authors.initials: JP
authors.lastname: Fededa
authors.affiliation: IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, 1030 Vienna, Austria.
authors.forename: Shane J
authors.initials: SJ
authors.lastname: Cronin
authors.affiliation: IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, 1030 Vienna, Austria.
authors.forename: Roberto
authors.initials: R
authors.lastname: Nitsch
authors.affiliation: Lead Discovery Center GmbH, D-44227 Dortmund, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Schultz-Fademrecht
authors.affiliation: Lead Discovery Center GmbH, D-44227 Dortmund, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Eickhoff
authors.affiliation: Lead Discovery Center GmbH, D-44227 Dortmund, Germany.
authors.forename: Sascha
authors.initials: S
authors.lastname: Menninger
authors.affiliation: Lead Discovery Center GmbH, D-44227 Dortmund, Germany.
authors.forename: Anke
authors.initials: A
authors.lastname: Unger
authors.affiliation: Max-Planck, Institute for Biochemistry, Department of Molecular Biology, D-82152 Martinsried, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Torka
authors.affiliation: Medical University Innsbruck, 6020 Innsbruck, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Gruber
authors.affiliation: Medical University Innsbruck, 6020 Innsbruck, Austria.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Hinterleitner
authors.affiliation: Medical University Innsbruck, 6020 Innsbruck, Austria.
authors.forename: Gottfried
authors.initials: G
authors.lastname: Baier
authors.affiliation: 1] Medical University Innsbruck, 6020 Innsbruck, Austria [2] Internal Medicine III, University Hospital Bonn, 53127 Bonn, Germany.
authors.forename: Dominik
authors.initials: D
authors.lastname: Wolf
authors.affiliation: Max-Planck, Institute for Biochemistry, Department of Molecular Biology, D-82152 Martinsried, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Ullrich
authors.affiliation: Lead Discovery Center GmbH, D-44227 Dortmund, Germany.
authors.forename: Bert M
authors.initials: BM
authors.lastname: Klebl
authors.affiliation: IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, 1030 Vienna, Austria.
authors.forename: Josef M
authors.initials: JM
authors.lastname: Penninger
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis / Q000188:drug therapy / Q000276:immunology* / Q000517:prevention & control; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D050721:Proto-Oncogene Proteins c-cbl / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D014859:Warfarin / Q000494:pharmacology / Q000627:therapeutic use; D000076202:c-Mer Tyrosine Kinase; D000094963:Axl Receptor Tyrosine Kinase
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000925:Anticoagulants; C118387:Cblb protein, mouse; D011518:Proto-Oncogene Proteins; D014859:Warfarin; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; C490767:Mertk protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; C513478:Tyro3 protein, mouse; D000076202:c-Mer Tyrosine Kinase; D000094963:Axl Receptor Tyrosine Kinase; C000722290:AXL receptor tyrosine kinase, mouse