Sustained Inflammatory Signalling through Stat1/Stat2/IRF9 Is Associated with Amoeboid Phenotype of Melanoma Cells

SIMPLE SUMMARY: Treatment of metastatic cancer is complicated by the ability of cancer cells to utilize various invasion modes when spreading through the body. Here, we studied the transition of melanoma cells between the round, amoeboid and elongated, mesenchymal invasion modes. Our results show that inflammatory signalling, which is commonly upregulated in the tumour microenvironment, is associated with the amoeboid phenotype of cancer cells. Treatment of melanoma cells with interferon beta promotes the amoeboid invasion modes and individual invasion. This suggests that inflammation associated signalling contributes to cancer cell invasion plasticity. ABSTRACT: The invasive behaviour of cancer cells underlies metastatic dissemination; however, due to the large plasticity of invasion modes, it is challenging to target. It is now widely accepted that various secreted cytokines modulate the tumour microenvironment and pro-inflammatory signalling can promote tumour progression. Here, we report that cells after mesenchymal–amoeboid transition show the increased expression of genes associated with the type I interferon response. Moreover, the sustained activation of type I interferon signalling in response to IFNβ mediated by the Stat1/Stat2/IRF9 complex enhances the round amoeboid phenotype in melanoma cells, whereas its downregulation by various approaches promotes the mesenchymal invasive phenotype. Overall, we demonstrate that interferon signalling is associated with the amoeboid phenotype of cancer cells and suggest a novel role of IFNβ in promoting cancer invasion plasticity, aside from its known role as a tumour suppressor.