Neoplastic cells are exposed to environmental stresses in both solid and hematopoietic tumors, and alter their metabolic programs to adapt to these challenging conditions. The purpose of the Metabolism Core is to provide advice, training, and equipment and reagents essential to the inquiries outlined in Projects 1, 2 and 3 of this proposal. The Core is structured to assist with experiments that use state-of-the-art, high-resolution LC- MS techniques to analyze the uptake, synthesis and metabolism of glucose, glutamine, lipids and other molecules. In addition, extensive lipidomic profiling will provide extensive analysis of lipid composition, synthesis, desaturation, and ?-oxidation. Finally, changes in NADH and NADPH production, oxygen consumption, ROS formation and mitochondrial function can be measured in living cells under different environmental conditions, including a range of oxygen tensions. The Core also provides specialized low- oxygen incubators and workstations that recapitulate key aspects of solid tumor microenvironments, as well as histopathological services for evaluating cell structure, proliferation, survival, and gene expression in primary tumors. Previous publications from Projects 1, 2, and 3 have demonstrated that oncogenic transformation commits cells to metabolic programs that support dysregulated cell growth, even under harsh microenvironmental conditions that suppress metabolic activity in normal cells. Projects 1, 2, and 3 are focused on understanding how cancer cells couple stress responses and altered metabolic activity to ensure cell survival and growth. For example, multiple different cancer cell lines require exogenous unsaturated lipids to support membrane biogenesis, avoid ER stress, and survive under hypoxic conditions. These data suggest that inhibiting lipid desaturation and/or scavenging could selectively kill cancer cells (Projects 1, 2, 3). Moreover, how specific effectors of the unfolded protein response (UPR) regulate tumor progression, as well as cell survival or apoptosis, in melanoma and other tumor types is a primary focus of Projects 2 and 3. How hypoxia modulates lipid synthesis and scavenging in response to specific oncogenic events and cellular stresses is also of primary interest to Projects 1 and 2. Histopathological support available through Core B will also be essential for the analysis of murine and human tumors (Projects 2 and 3). The technical resources provided by Core B will be instrumental in facilitating the experimental progress of all three Projects.
Core B provides state-of-the-art techniques and equipment for the measurement and quantification of a broad array of cellular metabolites and macromolecules, many of which play a critical role in cancer cell growth and survival. In addition, Core B operates and maintains specialized incubators and workstations that mimic the low-oxygen microenvironment of solid tumors, as well as sophisticated pathological services for the analysis of experimentally generated tumor tissues.
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