Snail mediates repression of the Dlk1-Dio3 locus in lung tumor-infiltrating immune cells

The epithelial-mesenchymal transition-inducing transcription factor Snail contributes to tumor progression in different malignancies. In the present study, we used a transcriptomics approach to elucidate the mechanism of Snail-mediated tumor growth promotion in a KrasLSL-G12D/+;p53fl/fl mouse model of lung adenocarcinoma. We discovered that Snail mediated the downregulation of the imprinted Dlk1-Dio3 locus, a complex genomic region containing protein-coding genes and non-coding RNAs that has been linked to tumor malignancy in lung cancer patients. The Dlk1- Dio3 locus repression mediated by Snail was found to occur specifically in several populations of tumor-infiltrating immune cells. It could be reproduced in primary splenocytes upon ex vivo culture with conditioned medium from Snail-expressing cancer cell lines, which suggests that a Snail-induced soluble factor secreted by the cancer cells mediates the Dlk1-Dio3 locus repression in immune cells, particularly in lymphocytes. Our findings furthermore point towards the contribution of Snail to an inflammatory tumor microenvironment, which is in line with our previous report of the Snail-mediated recruitment of pro-tumorigenic neutrophils to the lung tumors. This underlines an important role for Snail in influencing the immune compartment of lung tumors and thus contributing to disease progression.