Project Summary/Abstract: Melanoma is the leading cause of skin cancer deaths because it metastasizes efficiently to distant organs. Metastasis requires significant plasticity for cancer cells to survive the metabolic barriers distinct from the original primary tumor site including higher oxidative stress, limited nutrient availability, and changing microenvironments. The specific metabolic changes required for melanoma to undergo this process are poorly understood. We recently identified a novel suppressor of melanoma metastasis, the enzyme glyceraldehyde 3- phosphate dehydrogenase, spermatogenic (GAPDHS). We characterized the functional role of GAPDHS in a patient-derived xenograft (PDX) model and demonstrated its impact on glycolysis and pyruvate carboxylase activity. In this proposal, we will investigate the metabolic changes associated with GAPDHS that drive metastasis and determine whether its expression can be used to predict tumor progression in melanoma patients. Specifically, we will determine whether the enzymatic activity of GAPDHS in central glycolysis is required for suppressing metastasis (Aim 1), if its downstream suppression of pyruvate carboxylase activity influences metastasis (Aim 2), and whether GAPDHS expression serves as a biomarker of melanoma metabolism and metastasis in patients (Aim 3). As an Assistant Professor of Dermatology at the University of Texas Southwestern Medical Center, I devote 80% of my time to my research interests under the mentorship of Dr. Ralph DeBerardinis, with the remaining time dedicated to clinical practice. My goal is to transition to a career as a successful independent investigator overseeing my own laboratory and research program. To achieve this, I am seeking a K08 award to provide support for an additional period of mentored research to gain experience with cancer metabolism, biomarker development, and advanced biostatistics, which are all necessary to achieve my research goals. With the guidance of a distinguished mentorship committee, I will have access to the training, resources, and support necessary to establish a successful independent research program focused on identifying metabolic vulnerabilities in melanoma metastasis.

Project Narrative: Melanoma is the deadliest type of skin cancer because it rapidly and widely metastasizes. While cancer cells require significant metabolic rewiring for metastasis, the metabolic pathways essential for melanoma metastasis are poorly understood. Here, we propose to identify the critical metabolic functions of the metastatic suppressor GAPDHS (glyceraldehyde 3-phosphate dehydrogenase, spermatogenic) and determine its role in melanoma patients.