Grant: Operating Grant

Under normal conditions, cells require signals from their surroundings in order to grow, to move, or just to survive. These processes are essential for normal development, but they can be hijacked in cancer cells, allowing the disease to grow and spread. We are interested in a molecule called RET, that resides at the cell surface and helps convey these messages (signals) from outside the cell as part of its normal roles in development of a number of tissues. However, in some cancers, such as tumours of the pancreas, RET can also help tumour cells to spread by following a trail of signals that lead them to surround nerves lying close to the tumour (perineural invasion), causing pain and making the disease hard to treat. The RET molecule comes in two main forms, but our studies suggest that one form, called RET51, is more able to cause cancer cells to spread because it is enriched at the cell surface, thereby increasing its response to signals, which makes it an attractive target for therapies in several hard to treat cancers. Thus, our goals are to elucidate mechanisms that concentrate RET51 at the cell surface and determine how these contribute to its roles in the growth and spread of human cancers. We will do this by identifying the location of RET51 within or on human cancer cells and its abilities to induce these cells to move away or to invade their environment, particularly along nerves. Using an array of visualization methods and molecular tools we have developed we will explore the key mechanisms and protein interactions by which RET51 can promote cancer cell motility and invasiveness. Finally, we will characterize the expression of RET in prostate and colon cancers, where perineural invasion is linked with poor outcomes, to see if RET plays a role in this process. Our studies will clarify the mechanisms of RET-mediated tumour cell dissemination and provide additional tools with which to target this complicated system to combat human cancer.