A genome-wide screen in mice to identify cell-extrinsic regulators of pulmonary metastatic colonisation

Abstract

<jats:title>ABSTRACT</jats:title><jats:p>Metastatic colonisation, whereby a disseminated tumour cell is able to survive and proliferate at a secondary site, involves both tumour cell-intrinsic and -extrinsic factors. To identify tumour cell-extrinsic (microenvironmental) factors that regulate the ability of metastatic tumour cells to effectively colonise a tissue, we performed a genome-wide screen utilising the experimental metastasis assay on mutant mice. Mutant and wildtype (control) mice were tail vein-dosed with murine metastatic melanoma B16-F10 cells and 10 days later the number of pulmonary metastatic colonies were counted. Of the 1,300 genes/genetic locations (1,344 alleles) assessed in the screen 34 genes were determined to significantly regulate pulmonary metastatic colonisation (15 increased and 19 decreased; <jats:italic>P</jats:italic>&lt;0.005 and genotype effect &lt;-60 or &gt;+60). Whilst several of these genes have known roles in immune system regulation (<jats:italic>Bach2, Cyba, Cybb, Cybc1, Id2, Igh-6, Irf1, Irf7, Ncf1, Ncf2, Ncf4</jats:italic> and <jats:italic>Pik3cg</jats:italic>) most are involved in a disparate range of biological processes, ranging from ubiquitination (<jats:italic>Herc1</jats:italic>) to diphthamide synthesis (<jats:italic>Dph6</jats:italic>) to Rho GTPase-activation (<jats:italic>Arhgap30</jats:italic> and <jats:italic>Fgd4</jats:italic>), with no previous reports of a role in the regulation of metastasis. Thus, we have identified numerous novel regulators of pulmonary metastatic colonisation, which may represent potential therapeutic targets.</jats:p>