Author: ["Louise van der Weyden","Mark J. Arends","Andrew D. Campbell","Tobias Bald","Hannah Wardle-Jones","Nicola Griggs","Martin Del Castillo Velasco-Herrera","Thomas Tüting","Owen J. Sansom","Natasha A. Karp","Simon Clare","Diane Gleeson","Edward Ryder","Antonella Galli","Elizabeth Tuck","Emma L. Cambridge","Thierry Voet","Iain C. Macaulay","Kim Wong","Sarah Spiegel","Anneliese O. Speak","David J. Adams"]
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Abstract
Screening mutant mouse lines using a genome-wide in vivo assay identifies microenvironmental regulators of metastatic colonization and defines SPNS2 as an important mediator of lung colonization. The multistep process of the metastastic colonization of tumours is influenced by the tissue and systemic microenvironment. From a screen of mutant mouse lines to identify microenvironmental modulators, David Adams, Anneliese Speak and colleagues identify SPNS2 as an important mediator of lung colonization. Deletion of Spns2 promotes tumour cell killing by natural killer cells and effector T cells, reducing the metastatic burden in mouse cancer models. 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 system1). 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 outcome2. 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.Cite this article
van der Weyden, L., Arends, M., Campbell, A. et al. Genome-wide in vivo screen identifies novel host regulators of metastatic colonization. Nature 541, 233–236 (2017). https://doi.org/10.1038/nature20792 