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Genome-wide in vivo screen identifies novel host regulators of metastatic colonization.
van der Weyden, Louise; Arends, Mark J; Campbell, Andrew D; Bald, Tobias; Wardle-Jones, Hannah; Griggs, Nicola; Velasco-Herrera, Martin Del Castillo; Tüting, Thomas; Sansom, Owen J; Karp, Natasha A; Clare, Simon; Gleeson, Diane; Ryder, Edward; Galli, Antonella; Tuck, Elizabeth; Cambridge, Emma L; Voet, Thierry; Macaulay, Iain C; Wong, Kim; Spiegel, Sarah; Speak, Anneliese O; Adams, David J.
Afiliação
  • van der Weyden L; Wellcome Trust Sanger Institute, Wellcome Genome Campus, Cambridge CB10 1SA, UK.
  • Arends MJ; University of Edinburgh Division of Pathology, Edinburgh Cancer Research UK Cancer Centre, Institute of Genetics &Molecular Medicine, Edinburgh EH4 2XR, UK.
  • Campbell AD; Cancer Research UK Beatson Institute, Glasgow G61 1BD, UK.
  • Bald T; Department of Dermatology, University Hospital Magdeburg, Magdeburg 39120, Germany.
  • Wardle-Jones H; Department of Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston 4006, Australia.
  • Griggs N; Wellcome Trust Sanger Institute, Wellcome Genome Campus, Cambridge CB10 1SA, UK.
  • Velasco-Herrera MD; Wellcome Trust Sanger Institute, Wellcome Genome Campus, Cambridge CB10 1SA, UK.
  • Tüting T; Wellcome Trust Sanger Institute, Wellcome Genome Campus, Cambridge CB10 1SA, UK.
  • Sansom OJ; Department of Dermatology, University Hospital Magdeburg, Magdeburg 39120, Germany.
  • Karp NA; Cancer Research UK Beatson Institute, Glasgow G61 1BD, UK.
  • Clare S; Wellcome Trust Sanger Institute, Wellcome Genome Campus, Cambridge CB10 1SA, UK.
  • Gleeson D; Wellcome Trust Sanger Institute, Wellcome Genome Campus, Cambridge CB10 1SA, UK.
  • Ryder E; Wellcome Trust Sanger Institute, Wellcome Genome Campus, Cambridge CB10 1SA, UK.
  • Galli A; Wellcome Trust Sanger Institute, Wellcome Genome Campus, Cambridge CB10 1SA, UK.
  • Tuck E; Wellcome Trust Sanger Institute, Wellcome Genome Campus, Cambridge CB10 1SA, UK.
  • Cambridge EL; Wellcome Trust Sanger Institute, Wellcome Genome Campus, Cambridge CB10 1SA, UK.
  • Voet T; Wellcome Trust Sanger Institute, Wellcome Genome Campus, Cambridge CB10 1SA, UK.
  • Macaulay IC; Wellcome Trust Sanger Institute, Wellcome Genome Campus, Cambridge CB10 1SA, UK.
  • Wong K; Department of Human Genetics, University of Leuven (KU Leuven), Leuven, 3000, Belgium.
  • Spiegel S; Wellcome Trust Sanger Institute, Wellcome Genome Campus, Cambridge CB10 1SA, UK.
  • Adams DJ; Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, Virginia 23298-0614, USA.
Nature ; 541(7636): 233-236, 2017 01 12.
Article em En | MEDLINE | ID: mdl-28052056
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.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Genoma / Proteínas de Transporte de Ânions / Neoplasias Pulmonares / Metástase Neoplásica Limite: Animals Idioma: En Ano de publicação: 2017 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Genoma / Proteínas de Transporte de Ânions / Neoplasias Pulmonares / Metástase Neoplásica Limite: Animals Idioma: En Ano de publicação: 2017 Tipo de documento: Article