Grant: Project Grant

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 cell surface molecule called RET that helps convey messages (signals) from outside the cell as part of its normal roles in tissue development. 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 leads them to move toward and along nerves that lie close to the tumour (perineural invasion). In response to these signals, RET can cause cancer cells to detach from the main tumour, move through surrounding tissues and invade the nerve, making the disease hard to treat and causing the patient much pain. These roles make RET an attractive target for therapies to reduce cancer spread. Here, we aim to elucidate mechanisms that contribute to RET's roles in cancer invasion and spread. We will do this using a panel of human pancreatic cancer cell lines, and well established visualization methods and molecular tools that we have developed to identify the key protein interactions and signals RET requires to promote invasion. Once we have identified these, we will evaluate their contributions to RET's roles in in vivo pancreatic cancer growth, nerve invasion and spread to other distant sites. We will also determine whether blocking or reducing these signals can prevent cancer invasion and reduce the pain it causes when these cells are grown in vivo. Finally, we are designing a new kind of virus therapy that can specifically attack RET-expressing tumours as a way to address these processes. Our studies will establish the mechanisms of RET-mediated tumour cell dissemination and provide additional tools and therapeutic opportunities to address this complicated problem and combat human cancer spread.