Project 444160

Metastasis is the dissemination of cancer cells from their birthplace in the body to distant organs. As it turns out, this is an inefficient process. Of the millions of cells in the primary tumor, only a small subset manage to gain access to the lymphatic or circulatory systems and an even smaller fraction ever colonize a distant site or grow into a clinically relevant tumor. Unfortunately, the inefficiency of the process does not lessen its devastating effects: metastatic stage cancer is very difficult to treat and remains a critical problem in medicine. In this grant proposal, we describe how we will study the ways in which cancer cells become metastatic. There are three key potential mechanisms that have previously been linked to metastatic behavior. The first involves changes to the physical characteristics of the tumor cells, in a way that promotes cell invasion and migration. The second mechanism involves the regulation of gene expression through reversible marks left on the genome, called epigenetic alterations. The third mechanism involves immune cell infiltration into the tumor, which generates inflammation and immune suppression. We have developed a new model system to study the metastasis of melanoma, an aggressive cancer of the pigment cells. What is unique about our model is that the melanoma begins within the eyes and then spreads to the liver and lungs. This type of cancer is called uveal melanoma. It is the most common eye cancer and it is deadly. Uveal melanoma metastasizes in half of all patients, after which there is no effective treatment. A better understanding of the ways that cancer cells escape the primary tumor and adapt to survive in different parts of the body will help us develop more effective therapies for late stage cancers.