PROJECT SUMMARY/ABSTRACT Metastatic melanoma is the cause of over 80% of skin cancer deaths. Previous work in our lab interrogating the molecular differences between highly and poorly metastatic melanoma cells revealed that expression of the secreted protein apolipoprotein E (APOE) is repressed in aggressive melanomas through microRNA targeting. Rescuing APOE expression through genetic and pharmacologic approaches suppresses metastatic phenotypes and prolongs survival in melanoma animal models. Suppression of the invasion phenotype in particular was found to be mediated by low-density lipoprotein receptor-related protein 1 (LRP1), an APOE receptor present on the melanoma cell surface. However, the mechanisms by which LRP1 cooperates with APOE to facilitate inhibition of melanoma invasion remain uncharacterized. This proposal seeks to elucidate the molecular alterations initiated by this APOE-LRP1 interaction that result in loss of melanoma invasive capacity. Based on literature evidence and preliminary data, I hypothesize that APOE inhibits melanoma invasiveness by activating an LRP1 signaling axis. This hypothesis will be tested through the following two aims: In Aim 1, I will fully characterize the functional consequences of LRP1 loss on APOE-mediated metastasis suppression by developing LRP1 genetic knockouts in melanoma cell lines and performing metastasis assays as well as transcriptomic analysis. In Aim 2, I will explore the role of LRP1 intracellular signaling as a potential suppressive mechanism downstream of APOE binding by developing LRP1 signaling mutants in melanoma cell lines and in a genetic mouse melanoma model. Successful completion of these studies will uncover a novel, therapeutically targetable signaling pathway that regulates melanoma metastasis and will further our understanding of the influences of APOE and LRP1 on cancer progression. Training will be completed in the laboratory of Dr. Sohail Tavazoie and the highly collaborative environments of The Rockefeller University and the Tri-Institutional MD- PhD Program, and will be centered on my goal of becoming an independent physician-scientist.