Impact of elevated insulin signaling on imaginal disc cells in Drosophila

Speaker: Dr Hugo Stocker, Institute of Molecular Systems Biology, ETH Zürich, Switzerland
Host: Kim Rewitz, Section for Cell- and Neurobiology

Abstract
The closely linked insulin-PI3K and TORC1 signaling pathways are key regulators of cellular growth. Their main negative regulators are the tumor suppressors Pten and Tsc1/2, respectively. Whereas the loss of Pten is associated with many human cancer types, mutations in Tsc1/2 rather result in benign hamartomas. We have established a model for early tumorigenic stages in imaginal discs of Drosophila melanogaster. Upon nutrient restriction (NR), cells mutant for Pten shift from hypertrophy to massive hyperplasia, resulting in overgrown organs almost completely composed of Pten mutant tissue. Unlike Pten mutant cells, cells lacking Tsc1 do not display a hyperproliferative behavior upon NR; the observed overgrowth of the affected organs is exclusively caused by hypertrophy. Our genetic analysis demonstrates that the transcription factor FoxO acts as a proliferation brake in Tsc1 mutant cells. Furthermore, we also observed precocious differentiation of Tsc1 FoxO double mutant imaginal disc cells into adult tissues. To understand the mechanisms underlying the hyperproliferation of Pten mutant cells upon NR, we analyzed transcriptional changes in eye imaginal discs mostly composed of Pten mutant tissue as compared to wild-type discs by means of RNAseq. Our analysis revealed 112 genes differentially responding to NR in Pten mutant cells. We are currently testing these differentially expressed genes for their influence on the overgrowth caused by the loss of Pten.