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Dynamic, stem cell-mediated self-renewal in the Drosophila intestine

Final Report Summary - DYNASTEM (Dynamic, stem cell-mediated self-renewal in the Drosophila intestine.)

The DynaStem project (ERC Advanced Grant 268515) used advanced genetics to address the mechanisms of gut epithelial regeneration in the fruit fly, Drosophila melanogaster. The similarities between mechanisms of gut homeostasis in flies and man suggest that many of the genes and regulatory interactions discovered using Drosophila genetics experiments may be relevant to human biology, particularly so to diseases that involve deregulated stem cell growth. For instance, these studies provided new potential biomarkers and gene targets that could eventually be used for the diagnosis and treatment of inflammation and colorectal and lung cancers, and for regenerative therapies. A general goal of the project was to identify genes and cell signaling pathways that play important regulatory roles in gut epithelial damage sensing, stem cell activation, and regeneration of the gut epithelium. The project proceeded essentially according to plan and many new things were discovered and reported in the scientific literature. Genetic screening identified many new genes and several processes that regulate intestinal stem cell activation for proliferation. For instance we identified the genes Cic, Pnt, and Ets21C as novel, critical effectors of EGFR/RAS signaling, a pathway that is frequently activated in a wide range of human cancers. Similarly, many new genes and several processes were identified that are used by gut epithelial cells to sense damage, the initiating trigger for stem cell activation and epithelial regeneration. For instance we identified important roles for reactive oxygen signaling, integrin-mediated cell adhesion, JNK, and P38 signaling in gut epithelial damage sensing. In both instances most of the genes and pathways we uncovered in Drosophila have highly homologous counterparts in humans, and the likelihood that these genes and functions have critical roles in human gut homeostasis and other epithelial tissues is very high. In this respect our studies serve as lead research, providing testable models and specific target genes for scientists and doctors who are researching the biology of the human digestive tract and the diseases, such as colorectal cancer, which impact it.