Understanding cell migration in health and disease

The ability of cells to adhere and migrate is integral to the physiological function of tissues. Signals that determine the motile state of cells can derive from the extracellular matrix environment or from intracellular signals. Any aberration in interpretation of such signals can lead to diseases including cancer and inflammation. Correction of these aberrations can be a powerful tool for preventing disease and promoting regeneration, which however requires a profound understanding of the signals that regulate cell motility.

A critical determinant of cell motility is the state of cell adhesion mediated by so-called focal adhesions in cells. In focal adhesions cell adhesion receptors (integrins) are linked to the contractile actin-myosin cytoskeleton through a large complex of proteins, the focal adhesion plaque proteins. This network of the plaque proteins consists of a number of structural and signalling proteins, which receives and sends signals to other cellular compartments. How this signalling network is regulated is unclear.

CRISPR mediated genome editing has been described by the journal “Science” as the “Breakthough of the Year 2015” technology. CRISPR facilitates knock out of genes and we propose to use it here in screens to identify important genes involved in the regulation polarised cell migration. We will use a CRISPR genomic library for gene knockout in highly migratory cells. By screening for changes in their motile behaviour (cell migration assays and invasion assays), we will identify those genes that either promote or decrease cell migration. In additional sets of experiments we will examine the impact of the genes on the composition and dynamics of focal adhesions.

A hallmark of cancer cells is misinterpretation of external signals that lead to deficiencies in cell polarity. We hypothesise that cells altered in cell motility are also perturbed in the interpretation of polarisation signals that promote directional healthy migration. To examine the effect of gene knockout on cell polarity, we will plate them on micro-patterned substrates that in wild-type cells induce defined cell polarity features. In a final set of experiments we aim to rescue cell motility and polarity by knock-in of the original gene. We will introduce mutations in order to identify the critical regions that help us to reveal signalling pathways that control cell motility.

Overall, the project will provide us with detailed information of how cell motility is regulated in health and disease.

Timeline:
Please note that the timeline for all studentships will be: Year 1 – University of Manchester, Year 2/3 - WIS, Year 4 - University of Manchester.