METABOLISM CORE Abstract The metabolism core of the proposed the UNMC Acquired Resistance to Therapy Network (ARTNet) Center for Pancreatic Cancer (ACPC) will study innovative, hypothesis-driven mechanisms of metabolic and signaling alterations that contribute to acquired therapy resistance in pancreatic ductal adenocarcinoma (PDAC). The core services provided by the metabolism core will be well integrated into all the three projects. The core will offer cost-effective metabolomics and data analysis support with appropriate quality controls for all projects by providing a centralized infrastructure and expertise in metabolomics, physiological assays, and metabolic dependency/vulnerability screens. The metabolism core will have three specific aims. The basic capabilities offered by the Core will include steady-state polar metabolomics and lipidomics (Specific Aim 1), Stable Isotope Resolved Metabolomics (SIRM) with kinetic flux analysis (Specific Aim 2), and Seahorse extracellular flux analyzer-based assays, fluorescent assays to investigate the metabolic state of cells, and identifying metabolic vulnerabilities (Specific Aim 3). The Metabolism Core will participate in the design and conduct of steady-state polar metabolomics, lipidomics, 13C-metabolite labeled kinetic flux analysis with cell lines, organoids, and exosomes. The core will also perform steady-state polar metabolomics and lipidomics for mouse and human tumor tissue specimens in all the projects. The core will also provide hands-on training, as needed, for the ACPC, other ARTNet centers, and other investigators. The core will also provide support for measuring drug concentrations and metabolism in the tissues and drug pharmacokinetics/ pharmacodynamics studies.