PROJECT SUMMARY Metabolic rewiring is essential for cancer cell survival and metabolic dysfunction re-emerged as a hallmark for cancer. However, our current knowledge of metabolic pathways and the regulation in cancer is still limited. Striking improvements in mass spectrometry and metabolic flux analysis has greatly improved our ability to quantify metabolism leading to novel treatment strategies. With this NCI Research Specialist Award, we aim to establish a protected position for Thekla Cordes for 5 years to support research for Prof. Christian Metallo at the University of California, San Diego. Thekla Cordes is an expert in dissecting cancer metabolism by applying metabolic systems biology approaches and will be key personnel to complete current and future research goals of NCI-funded research projects. Her research aims to identify and exploit metabolic vulnerabilities in cancer and will mainly support the R01CA234245 grant “Non-essential amino acids and sphingolipid diversity in cancer progression”. Specifically, she will 1) develop and apply mass spectrometry-based analytical approaches to quantify metabolite levels and metabolic fluxes in diverse cancer settings. She will focus on 13C, 15N, and 2H tracing approaches to trace central carbon, lipid, and redox metabolism. She will then 2) establish anchorage- independent cell culture models to better mimic the tumor environment. Further, she will engineer cell lines with genetically altered metabolic pathways focusing on amino acid (i.e. serine and alanine) and sphingolipid metabolism (i.e. serine palmitoyl transaminase (SPT). Finally, she will 3) combine tracer and culture approaches to gain insights into biochemical and mechanistic understanding of metabolic reprograming in cancer. We expect that Thekla Cordes’ expertise in metabolic flux approaches and pathway study will provide critical new insights into cancer metabolism and will nucleate new exciting research directions impacting the broad field of cancer biology. Ultimately, her support, scientific expertise, and results are expected to substantially advance the development of new and improved therapeutic strategies to combat cancer.