Uveal melanoma (UM) is the deadliest form of adult eye cancer in the U.S. Tumors that have formed in the eye can often be removed or treated successfully, but after 1 to 20 years, approximately 50 percent of patients are diagnosed with metastatic UM tumors (tumors that have spread from the eye). Once the disease had spread to another organ site such as the liver, which is most common for UM, disease prognosis is often poor due to the lack of effective treatment options. Metastatic UM responds poorly to many therapeutic options. It is unclear how UM spreads to the liver. Previous studies have found that alterations in the BRCA1-associated protein 1(BAP1) gene in tumor cells are associated with elevated risks of UM metastasis. These alterations abolish BAP1 presence and function in cells. However, the role of BAP1 in the metastasis of UM is not well studied. We and others have data showing that in the absence of BAP1, UM cells grow slower, compared to UM cells that have BAP1. In our research proposal, we will use molecular biology techniques to investigate what causes cells with loss of BAP1 to grow slowly and whether this facilitates cells to survive therapy and harsh conditions during spreading to another organ site. Since UM cells with loss of BAP1 develop into tumors at the secondary site (liver), we will investigate whether liver cells adjacent to UM cells in the liver have a role in enhancing UM cell growth to form into large aggressive tumors. The Principal Investigator of this study, Dr. Chua, is an early career researcher with a good record of accomplishment in cancer and UM research. She aims to be an established melanoma researcher capable of consistently producing high quality and impactful research. This research proposal addresses an important problem that is not well studied in UM. Outcomes from the research potentially have a significant impact and hence, will facilitate Dr. Chua in sustaining her career at the forefront of melanoma research. The milestones described in her Career Development and Sustainment Plan will also encourage her to improve on areas that will help her toward producing high impact and quality research. The outcomes from the proposed research will describe BAP1’s roles in controlling UM metastasis and will also show mechanisms associated with UM metastasis. Results from the study will likely lead to uncovering strategies to prevent UM metastasis and recurrence. Our long-term goal is to develop or find treatment agents that can be tested and ultimately used clinically to prevent tumor cells from forming into aggressive tumors at the secondary organ site. Through this strategy, we aim to prolong the lives of patients with UM. Despite the rarity of UM compared to skin melanoma, patient survival is poor once metastatic disease is diagnosed. Individuals with fairer eye color and/or increased exposure to ultraviolet radiation, including military personnel, are more susceptible to developing this disease. Hence, our studies addressing metastasis of UM will contribute toward the research, patient, and the military communities in the United States.