title: Genome-wide in vivo screen identifies novel host regulators of metastatic colonization.
abstract: Metastasis is the leading cause of death for cancer patients. This multi-stage process requires tumour cells to survive in the circulation, extravasate at distant sites, then proliferate; it involves contributions from both the tumour cell and tumour microenvironment ('host', which includes stromal cells and the immune system). Studies suggest the early steps of the metastatic process are relatively efficient, with the post-extravasation regulation of tumour growth ('colonization') being critical in determining metastatic outcome. Here we show the results of screening 810 mutant mouse lines using an in vivo assay to identify microenvironmental regulators of metastatic colonization. We identify 23 genes that, when disrupted in mouse, modify the ability of tumour cells to establish metastatic foci, with 19 of these genes not previously demonstrated to play a role in host control of metastasis. The largest reduction in pulmonary metastasis was observed in sphingosine-1-phosphate (S1P) transporter spinster homologue 2 (Spns2)-deficient mice. We demonstrate a novel outcome of S1P-mediated regulation of lymphocyte trafficking, whereby deletion of Spns2, either globally or in a lymphatic endothelial-specific manner, creates a circulating lymphopenia and a higher percentage of effector T cells and natural killer (NK) cells present in the lung. This allows for potent tumour cell killing, and an overall decreased metastatic burden.
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Genome Campus, Cambridge CB10 1SA, UK.
authors.forename: Louise
authors.initials: L
authors.lastname: van der Weyden
authors.affiliation: University of Edinburgh Division of Pathology, Edinburgh Cancer Research UK Cancer Centre, Institute of Genetics &Molecular Medicine, Edinburgh EH4 2XR, UK.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Arends
authors.affiliation: Cancer Research UK Beatson Institute, Glasgow G61 1BD, UK.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Campbell
authors.affiliation: Department of Dermatology, University Hospital Magdeburg, Magdeburg 39120, Germany.|Department of Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston 4006, Australia.
authors.forename: Tobias
authors.initials: T
authors.lastname: Bald
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Genome Campus, Cambridge CB10 1SA, UK.
authors.forename: Hannah
authors.initials: H
authors.lastname: Wardle-Jones
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Genome Campus, Cambridge CB10 1SA, UK.
authors.forename: Nicola
authors.initials: N
authors.lastname: Griggs
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Genome Campus, Cambridge CB10 1SA, UK.
authors.forename: Martin Del Castillo
authors.initials: MD
authors.lastname: Velasco-Herrera
authors.affiliation: Department of Dermatology, University Hospital Magdeburg, Magdeburg 39120, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Tüting
authors.affiliation: Cancer Research UK Beatson Institute, Glasgow G61 1BD, UK.
authors.forename: Owen J
authors.initials: OJ
authors.lastname: Sansom
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Genome Campus, Cambridge CB10 1SA, UK.
authors.forename: Natasha A
authors.initials: NA
authors.lastname: Karp
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Genome Campus, Cambridge CB10 1SA, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Clare
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Genome Campus, Cambridge CB10 1SA, UK.
authors.forename: Diane
authors.initials: D
authors.lastname: Gleeson
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Genome Campus, Cambridge CB10 1SA, UK.
authors.forename: Edward
authors.initials: E
authors.lastname: Ryder
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Genome Campus, Cambridge CB10 1SA, UK.
authors.forename: Antonella
authors.initials: A
authors.lastname: Galli
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Genome Campus, Cambridge CB10 1SA, UK.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Tuck
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Genome Campus, Cambridge CB10 1SA, UK.
authors.forename: Emma L
authors.initials: EL
authors.lastname: Cambridge
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Genome Campus, Cambridge CB10 1SA, UK.|Department of Human Genetics, University of Leuven (KU Leuven), Leuven, 3000, Belgium.
authors.forename: Thierry
authors.initials: T
authors.lastname: Voet
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Genome Campus, Cambridge CB10 1SA, UK.
authors.forename: Iain C
authors.initials: IC
authors.lastname: Macaulay
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Genome Campus, Cambridge CB10 1SA, UK.
authors.forename: Kim
authors.initials: K
authors.lastname: Wong
authors.affiliation: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, Virginia 23298-0614, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Spiegel
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Genome Campus, Cambridge CB10 1SA, UK.
authors.forename: Anneliese O
authors.initials: AO
authors.lastname: Speak
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Genome Campus, Cambridge CB10 1SA, UK.
authors.forename: David J
authors.initials: DJ
authors.lastname: Adams
mesh_terms: D000818:Animals; D027321:Anion Transport Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D004195:Disease Models, Animal; D005260:Female; D016678:Genome / Q000235:genetics*; D023281:Genomics; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology; D008175:Lung Neoplasms / Q000235:genetics* / Q000276:immunology / Q000473:pathology / Q000556:secondary*; D008231:Lymphopenia / Q000235:genetics / Q000473:pathology; D008246:Lysophospholipids / Q000378:metabolism; D008297:Male; D051379:Mice; D009362:Neoplasm Metastasis / Q000235:genetics* / Q000473:pathology*; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology; D059016:Tumor Microenvironment
chemical_list: D027321:Anion Transport Proteins; D008246:Lysophospholipids; C572630:Spns2 protein, mouse; C060506:sphingosine 1-phosphate; D013110:Sphingosine