Grant: Project Grant

Tumours are made up of cells that can be recognized by several changes they exhibit compared to normal cells. Some of these changes involve alteration in the abundance and function of proteins found on the tumour cells' outer surface. One of the types of cell surface proteins altered in cancer cells is hormone receptors, in particular one named Epidermal Growth Factor Receptor (EGFR). EGFR signals to cells to grow and migrate and when uncontrolled, these traits can lead to cancer and metastasis. EGFR is thus an attractive drug target for the development of novel therapies for the treatment of hard-to-treat cancers such as triple-negative breast cancer. Importantly, we discovered that EGFR does not work alone, but requires assistance from a family of proteins called tetraspanins. Specifically, tetraspanin proteins form a network among one another called tetraspanin nanodomains on the surface of cells. We discovered that only EGFR that is engaged within tetraspanin nanodomains, representing ~10% of EGFR within a cell, can be activated to promote cell survival and proliferation. Understanding this novel mechanism that allows tetraspanin proteins to gate EGFR activation, a phenomenon which we have called signaling "licensing", is critical to allow development of better inhibitors to target EGFR in cancer. To uncover how tetraspanin nanodomains control the function of EGFR and thus cancer progression, we will use several different approaches including advanced microscopy. Specifically, we rely on a method called single-particle tracking that allowing us to "see" individual EGFR molecules, whether or not these are engaged within tetraspanin nanodomains, and thus resolve how EGFR is controlled. This research will reveal how tetraspanin nanodomains work within healthy and cancerous cells to control EGFR function. Since alterations in the normal function of EGFR cause cancer cells to grow and metastasize, this work may reveal new ways to treat various types of cancer.