The goal of this project is to train Dr. Zachary Stine in the laboratory of Dr. Chi Van Dang at the University of Pennsylvania. A comprehensive training plan has been developed for Dr. Stine that will increase his expertise in the techniques and theories of cancer metabolism, develop his ability to effectively communicate his science, expand his network of collaborators, and prepare him for academic independence, the pursuit of funding and finding an academic position. This project will prepare Dr. Stine to become independent academic investigator focusing on the role of oncogenes and their targets on cancer metabolism. Background and aims: Cancer cell metabolism is reprogrammed to meet elevated metabolic needs, with many tumors overexpressing MYC becoming dependent on Glutamine metabolism. The potential therapeutic target Kidney type Glutaminase (GLS), which catalyzes the first step in the conversion of Glutamine to TCA cycle intermediate, is alternatively spliced to form two isoforms with different cellular localization (GAC and KGA). The impact of these isoforms on tumor progression and cancer metabolism is not well understood.
Specific Aims : 1) Determine if the GAC isoform of GLS is required for growth of p493 cells due to its contributions to mitochondrial metabolism. 2) Define the requirement for the GAC isoform of Glutaminase for in vivo tumor growth. 3) Define the role of SFRS10 in MYC-controlled GLS alternative splicing. My preliminary studies indicate that the GLS isoform GAC is required for cancer cell growth. Metabolomics can give a global view of how Glutamine is used in metabolism. Altering GLS splicing to deplete GAC without downregulating total GLS mRNA, metabolomics will be used to determine the role of the GAC GLS isoform in cancer metabolism. It will also be determine if the GAC is required for xenograft tumor growth in vivo. The role of MYC control of GLS alternative splicing in metabolic reprogramming will be determined. Disease relevance: This proposal will provide insight into the role of glutaminase isoforms in cancer. Additionally, metabolic profiling will allow us to understand the metabolic impacts of the isoforms and will help us predict therapeutic response of to glutaminase inhibition based on isoform expression levels. This study will provide fundamental insights into the role of GLS isoforms in cancer metabolism in vitro and in vivo. In light of emerging splice modulation clinical trials, this is a valuable opportunity to explore anti-tumorigenic possibility of modulating GLS splicing in vivo. By altering GLS splicing in vivo, we may be able to reduce the side effects that arise from GLS inhibitors that target both isoforms.
Many cancer cells depend on the amino acid glutamine as a fuel source, with the enzyme Glutaminase catalyzing the first step of the conversion of glutamine to energy and building blocks. Glutaminase comes in a highly active short form and a less active long form. This study will determine the role of short and long Glutaminase in cancer metabolism, providing fundamental understanding of Glutamine metabolism to aid in the translation of Glutaminase inhibition to the clinic.
|Altman, Brian J; Stine, Zachary E; Dang, Chi V (2016) From Krebs to clinic: glutamine metabolism to cancer therapy. Nat Rev Cancer 16:619-34|
|Stine, Zachary E; Walton, Zandra E; Altman, Brian J et al. (2015) MYC, Metabolism, and Cancer. Cancer Discov 5:1024-39|
|Hsieh, Annie L; Walton, Zandra E; Altman, Brian J et al. (2015) MYC and metabolism on the path to cancer. Semin Cell Dev Biol 43:11-21|
|Altman, Brian J; Hsieh, Annie L; Sengupta, Arjun et al. (2015) MYC Disrupts the Circadian Clock and Metabolism in Cancer Cells. Cell Metab 22:1009-19|
|Xiang, Yan; Stine, Zachary E; Xia, Jinsong et al. (2015) Targeted inhibition of tumor-specific glutaminase diminishes cell-autonomous tumorigenesis. J Clin Invest 125:2293-306|
|Stine, Zachary E; Dang, Chi V (2015) Splicing and Dicing MYC-Mediated Synthetic Lethality. Cancer Cell 28:405-6|
|Le, Anne; Stine, Zachary E; Nguyen, Christopher et al. (2014) Tumorigenicity of hypoxic respiring cancer cells revealed by a hypoxia-cell cycle dual reporter. Proc Natl Acad Sci U S A 111:12486-91|
|Stine, Zachary E; Dang, Chi V (2013) Stress eating and tuning out: cancer cells re-wire metabolism to counter stress. Crit Rev Biochem Mol Biol 48:609-19|