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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
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University of Pennsylvania
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Zhang, Ji; Pavlova, Natalya N; Thompson, Craig B (2017) Cancer cell metabolism: the essential role of the nonessential amino acid, glutamine. EMBO J 36:1302-1315
Davis, Jeremy L; Langan, Russell C; Panageas, Katherine S et al. (2017) Elevated Blood Neutrophil-to-Lymphocyte Ratio: A Readily Available Biomarker Associated with Death due to Disease in High Risk Nonmetastatic Melanoma. Ann Surg Oncol 24:1989-1996
Xie, Hong; Simon, M Celeste (2017) Oxygen availability and metabolic reprogramming in cancer. J Biol Chem 292:16825-16832
Rozpedek, W; Nowak, A; Pytel, D et al. (2017) Molecular Basis of Human Diseases and Targeted Therapy Based on Small-Molecule Inhibitors of ER Stress-Induced Signaling Pathways. Curr Mol Med 17:118-132
Gannon, Patrick J; Akay-Espinoza, Cagla; Yee, Alan C et al. (2017) HIV Protease Inhibitors Alter Amyloid Precursor Protein Processing via ?-Site Amyloid Precursor Protein Cleaving Enzyme-1 Translational Up-Regulation. Am J Pathol 187:91-109
Ricca, Jacob; Turkekul, Mesruh; Barlas, Afsar et al. (2017) Validation of Anti-Mouse PDL-1 Goat Polyclonal Antibody Staining with Mouse PDL-1 In Situ Hybridization on Adjacent Sections of Cell Pellets and Mouse Tumors. Methods Mol Biol 1554:253-262
Sands, Stephen; Ladas, Elena J; Kelly, Kara M et al. (2017) Glutamine for the treatment of vincristine-induced neuropathy in children and adolescents with cancer. Support Care Cancer 25:701-708
Gade, Terence P F; Tucker, Elizabeth; Nakazawa, Michael S et al. (2017) Ischemia Induces Quiescence and Autophagy Dependence in Hepatocellular Carcinoma. Radiology 283:702-710
Palm, Wilhelm; Thompson, Craig B (2017) Nutrient acquisition strategies of mammalian cells. Nature 546:234-242
Pytel, Dariusz; Gao, Yan; Mackiewicz, Katarzyna et al. (2016) PERK Is a Haploinsufficient Tumor Suppressor: Gene Dose Determines Tumor-Suppressive Versus Tumor Promoting Properties of PERK in Melanoma. PLoS Genet 12:e1006518

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