ABSTRACT. This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA- 21-100. Organotropism is the affinity of metastatic cancer cells for specific organs. Among cancers that exhibit high degree of organotropism is uveal melanoma (UM), the most common intraocular malignancy in adults. UM has a conspicuous predilection to spread to the liver, and patients with liver metastases have the worst prognosis with a median survival less than 12 months. The mechanisms underlying the proclivity of UM to spread to the liver are unknown, yet are critical to our ability to prevent and treat metastatic UM with the aim of prolonging patient survival. As an ophthalmic surgeon, I was able to obtain enucleation specimens from patients with UM, and perform single-cell RNA sequencing, followed by biochemical and functional analyses. This enabled us to discover that UMs with low and high metastatic tendencies are not fundamentally distinct disease subtypes; rather primary tumors harbor subclones with different metastatic proclivities. We identified that loss of a key epigenetic regulator, Polycomb Repressive Complex 1 (PRC1), induced a transition from an indolent to an aggressive UM phenotype. While analyzing the genetic characteristics of metastatic specimens, I found that UM metastases in the liver have a different genomic profile, and worse prognosis, than those with extrahepatic metastases. This proposal aims to determine the molecular underpinnings of metastatic UM tropism to the liver. I will test the hypothesis that the spread of uveal melanoma to the liver is dictated by a pre-existing distinct phenotype in the primary tumor which is driven by loss of PRC1. Under Aim 1, I will employ single cell genomics to characterize intratumor heterogeneity in hepatic as well as extra-hepatic metastases. Under Aim 2, I will test whether loss of PRC1selectively promotes UM liver metastasis in transplantable mouse models of UM. By integrating genomic data from clinical specimens and functional validation in pre-clinical models, this work aims to understand the molecular basis underlying organotropism in metastatic UM. I am an Assistant Professor at Yale University School of Medicine within the first year of my tenure-track appointment. I have two outstanding mentors. Dr. Marcus Bosenberg is a clinician scientist with an extensive track record in training postdoctoral fellows and physician-scientists and will provide me with additional training in mouse modeling. Dr. Mario Sznol is an oncologist who specializes in the management of patients with metastatic melanoma. They will provide me with the mentorship and support to ultimately attain full scientific independence. My structured training and career development plans include coursework in mouse modelling and scientific writing, presentations at national meetings, and regularly scheduled career development meetings with my mentors. My clinical and surgical practice will enab...