The overall goal of this program is to characterize the molecular basis for tumor cell adaptation to limitations in oxygen and nutrients. Oxygen and/or nutrient deprivation develops as cells within solid tumors accumulate in excess of physiological numbers supportable by the existing vascular system. Therefore, developing tumors are typically subjected to oxygen limitation and nutrient deprivation. The accumulation of non-transformed cells is inhibited under these conditions because hypoxia/nutrient deprivation leads to the initiation of apoptosis. In contrast, most tumor cells are defective in their apoptotic response, and therefore, fail to engage programmed cell death. Our central hypothesis is that tumor cells both suppress apoptosis and alter their metabolism to survive until new blood vessels grow. The goal of Project 1 is to identify metabolic pathways that allow tumor cells to adapt and grow under these conditions. This project will determine how cells simultaneously activate beta-oxidation to support ATP production while maintaining the level of fatty acid synthesis required for cell growth during glucose deprivation. Project 1 will also examine how hypoxic tumor cells coordinate protein and lipid synthesis when hypoxia inducible factor (HIF) activation results in diversion of available glucose away from macromolecular synthesis into anaerobic glycolysis. The experiments outlined in Project 2 will focus on metabolic outcomes of c-Myc, mTOR, and p53 modulation by oxygen limitation and HIF activation. HIFs influence anabolic metabolism, proliferation, protein synthesis, and DNA repair in transformed cells via these central regulatory pathways. Experiments proposed in Project 3 are based on the hypothesis that PERK (as a sensor of cellular nutrient availability) functions as a critical pro-survival factor via activation of a transcriptional program that promotes cellular adaptation to nutrient restriction thereby facilitating tumor growth. In this project, the contribution of PERK to the regulation of redox homeostasis and lipid biosynthesis will be evaluated. Through collaborations facilitated by this program project, we will investigate mechanisms whereby glucose limitation (Project 1) and oxygen deprivation (Project 2) regulate cellular responses to the microenvironment. Finally, how this contributes to redox homeostasis and genome integrity will be evaluated in Project 3. All three projects will make frequent use of the Metabolic Core which will provide assays for the analysis of cellular bioenergetics and an Administrative Core which will provide administrative oversight, budgetary management, and the organization of meetings with the external advisory board. Extensive points of collaboration have already been established between all three projects in the previous funding cycle. We anticipate that our collective efforts will provide novel insights into metabolic changes that characterize malignant cell adaptation under conditions of decreased oxygen and nutrient availability.

Public Health Relevance

Cells within growing tumors frequently undergo metabolic adaptations to survive and proliferate in the face of inadequate vascular function. Information obtained from the proposed studies will allow the development of new anti-cancer drugs for the treatment of diseases such as renal and mammary carcinomas.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-RPRB-O (M1))
Program Officer
Spalholz, Barbara A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pennsylvania
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Rozpedek, W; Pytel, D; Mucha, B et al. (2016) The Role of the PERK/eIF2α/ATF4/CHOP Signaling Pathway in Tumor Progression During Endoplasmic Reticulum Stress. Curr Mol Med 16:533-44
Krishna, Shefali; Palm, Wilhelm; Lee, Yongchan et al. (2016) PIKfyve Regulates Vacuole Maturation and Nutrient Recovery following Engulfment. Dev Cell 38:536-47
Tschaharganeh, Darjus F; Lowe, Scott W; Garippa, Ralph J et al. (2016) Using CRISPR/Cas to study gene function and model disease in vivo. FEBS J 283:3194-203
Pavlova, Natalya N; Thompson, Craig B (2016) The Emerging Hallmarks of Cancer Metabolism. Cell Metab 23:27-47
Xu, Zhenhua; Bu, Yiwen; Chitnis, Nilesh et al. (2016) miR-216b regulation of c-Jun mediates GADD153/CHOP-dependent apoptosis. Nat Commun 7:11422
Pytel, D; Majsterek, I; Diehl, J A (2016) Tumor progression and the different faces of the PERK kinase. Oncogene 35:1207-15
Gade, Terence P F; Hunt, Stephen J; Harrison, Neil et al. (2015) Segmental Transarterial Embolization in a Translational Rat Model of Hepatocellular Carcinoma. J Vasc Interv Radiol 26:1229-37
Qiu, Bo; Ackerman, Daniel; Sanchez, Danielle J et al. (2015) HIF2α-Dependent Lipid Storage Promotes Endoplasmic Reticulum Homeostasis in Clear-Cell Renal Cell Carcinoma. Cancer Discov 5:652-67
Ye, Jiangbin; Palm, Wilhelm; Peng, Min et al. (2015) GCN2 sustains mTORC1 suppression upon amino acid deprivation by inducing Sestrin2. Genes Dev 29:2331-6
Mucaj, V; Lee, S S; Skuli, N et al. (2015) MicroRNA-124 expression counteracts pro-survival stress responses in glioblastoma. Oncogene 34:2204-14

Showing the most recent 10 out of 93 publications