The transcriptional response to tumorigenic polarity loss in Drosophila

The cavities and organs within our body are lined with epithelial cells, which connect to each other to form continuous barriers. These cells have a highly polarized structure in which different components are found at the top and bottom of cells. In the fruit fly and most other animals, three genes known as the Scribble module control the polarity of epithelial cells. If these genes are faulty, the cells lose their polarity, break the epithelial barrier, and grow rapidly to form a tumor. Most malignant tumors that form from epithelial cells have lost normal cell polarity, so understanding how the organization and growth of epithelial cells are linked is a critical question. It is not clear how the loss of cell polarity can drive tumor formation. Here, Bunker et al. used a technique called RNA sequencing to study the expression of genes in tumor cells that have mutations in the Scribble module. Hundreds of genes in the tumor cells had different levels of expression from the levels seen in normal fly cells. One of these is a gene called upd3, which was expressed much more highly in tumor cells than in normal cells. This gene activates a signaling pathway—called the JAK/STAT pathway—that promotes cell growth and division in many animals. Bunker et al. found that experimentally lowering the activity of the JAK/STAT pathway reduced the growth of the tumor cells that had lost normal polarity. Further experiments show that disrupting the layer of epithelial cells activates two other signaling pathways that work together to switch on the upd3 gene when cell polarity is lost. Proteins belonging to the Polycomb Group also control the expression of upd3 and other genes involved in cell growth by altering how genetic material is packaged in cells. The similarities between this response and the response to tissue damage suggest that the loss of polarity drives tumor formation through an unstoppable wound-healing reaction. Therefore, Bunker et al.'s findings link the formation of epithelial tumors to the signaling pathways that control the repair of damaged tissues.