Analysis of FGF-signalling mechanisms in controlling cell migration in Drosophila

The position of cells within a multi-cellular organism is strictly controlled. The tissue environment provides information that tells the cells whether to divide, become motile or stay where they are. This plasticity enables the organism to react upon changing conditions, like pathogen attack. Consequently, a failure of this regulation may lead to severe diseases. During cancer, for example, cells leave their assigned position in a tissue, become motile, invade and eventually destroy other tissues. Our knowledge about the regulators of cell motility is therefore crucial for the cure of such diseases.

Research on genetic model organisms has demonstrated that the molecular regulation of cell motility is very similar between flies and man. However the way these regulators govern cell motility on a biochemical and genetic level is not known. We are using the fruit fly as a model with the aim to identify the important regulators and their modes of action. This information will provide a basis to see how these mechanisms relate to pathogenic situations in humans. These results will lead to a better understanding of human diseases like cancer, and will eventually be instructive for the generation of new medical treatments.

Cell migration plays important roles in developing and adult organisms and failure to regulate migration events can result in severe diseases, including birth defects, immunological disorders and cancer. Great progress has been made in identifying signalling molecules and the cytoskeletal mechanisms that drive cell migration, but key questions remain open: how signals control migration in time and space and how the signal translate into cytoplasmic events that change the behaviour of the responding cells. We employ a highly tractable genetic model system to identify and analyse novel components of the molecular mechanism driving cell migration.

The specific goal of our research is to understand the molecular link between signalling and the local regulation of cell adhesion and the cytoskeleton. We are addressing this problem using a Drosophila embryo model and will dissect how Fibroblast Growth Factor (FGF) signalling controls mesoderm migration. We identified two novel FGF8-like growth factors and will now assess the cellular function of these factors. We will use genetics to investigate whether they act as permissive factors or as instructive cues, i.e. whether these molecules can act as chemo-attractants in vivo. The cell biological responses of living cells upon ectopic FGF expression will be monitored using high-resolution microscopy.

Our genetic approach identified a novel factor in mediating FGF-triggered cell shape changes: the fly orthologue of the human proto-oncogene ect2, called Pebble (Pbl). We now want to understand the mechanism by which Pbl links receptor-tyrosine kinase activation to changes in the cytoskeleton. We will perform structure-function analyses of Pbl with the aim of determining its functional interactions with other proteins in the pathway. Novel interacting proteins will be identified by genetic and proteomic approaches, followed by functional analyses of the respective genes. In addition to pbl, our previous genetic screens have already yielded additional candidate genes that we are currently analysing molecularly.

Migratory cells often derive from polarized epithelial tissues in a process called epithelial-mesenchymal transition (EMT). EMT occurs in many tissues of developing and adult organisms and its tight molecular control is crucial to prevent pathological situations, such as metastasis during carcinogenesis. We currently focus our research on molecules that have been implicated in cancer, e.g the proto-oncogene ect2. Our research using the Drosophila system will lead to a better understanding of the molecular control of EMT and cell migration and therefore help to address questions immediately relevant to biomedical applications.