Grant: Doctoral Research Award: Canada Graduate Scholarships

Every year, ~130 Canadians are diagnosed with uveal melanoma (UM), the most common cancer of the eye. For half of these patients, the cancer metastasizes, making treatment more challenging. Most UMs are initiated by a mutation in either the GNAQ or GNA11 gene, and almost all metastatic cases have a mutation in the BAP1 gene. Loss of BAP1 is strongly associated with worse patient outcomes and reduced survival. But, how BAP1 loss promotes metastasis is not yet clear. The main goal of my project is to learn why BAP1 loss leads to accelerated metastasis. One of the mechanisms my project will investigate is Epithelial to Mesenchymal Transition (EMT), which has been shown in our lab's preliminary data to be associated with UM metastasis. EMT allows cancer cells to migrate and invade tissues by converting epithelial cells to mesenchymal cells. However, the most lethal state is the intermediate state between the epithelial and mesenchymal states. In this grey area, tumor cells are plastic and can easily adapt to new environments, which is key to metastatic success. The goal of my project is to identify the EMT state of subpopulations of tumor cells that successfully metastasized to various tissues. I will study the presence of EMT-like programs using single-cell RNA sequencing in human primary tumors and metastases. To further study this acquired versatility, I will analyze human ChIP-seq data to find which genes are kept in a "ready position" allowing them to undergo changes in response to EMT quickly. Another project component is exploring protein level changes when BAP1 is lost in UM. BAP1 removes a modification called ubiquitin from other proteins involved in DNA repair, cell death, and gene expression. By comparing which proteins are most affected by the loss of BAP1, I hope to identify potential therapeutic targets to mitigate or prevent UM metastasis, thus improving patient outcomes. This research can potentially impact other cancers involving EMT and BAP1 loss.