Tissue of Origin Dictates GOT1 Dependence and Confers Synthetic Lethality to Radiotherapy
Barbara S. Nelson, et al.
Received Date: 18th July 19
Barbara S. Nelson, Lin Lin, Daniel M. Kremer, Cristovão M. Sousa, Cecilia CottaRamusino, Amy Myers, Johanna Ramos, Tina Gao, Ilya Kovalenko, Kari Wilder-Romans, Joseph Dresser, Mary Davis, Ho-Joon Lee, Zeribe C. Nwosu, Scott Campit, Oksana Mashadova, Brandon N. Nicolay, Zachary P. Tolstyka, Christopher J. Halbrook, Sriram Chandrasekaran, John M. Asara, Howard C. Crawford, Lewis C. Cantley, Alec C. Kimmelman, Daniel R. Wahl, Costas A. Lyssiotis
Metabolic programs in cancer cells are influenced by genotype and the tissue of origin. We have previously shown that central carbon metabolism is rewired in pancreatic ductal adenocarcinoma (PDA) to support proliferation through a glutamate oxaloacetate transaminase 1 (GOT1)-dependent pathway. Here we tested if tissue type impacted GOT1 dependence by comparing PDA and colorectal cancer (CRC) cell lines and tumor models of similar genotype. We found CRC to be insensitive to GOT1 inhibition, contrasting markedly with PDA, which exhibit profound growth inhibition upon GOT1 knockdown. Utilizing a combination of metabolomics strategies and computational modeling, we found that GOT1 inhibition disrupted glycolysis, nucleotide metabolism, and redox homeostasis in PDA but not CRC. These insights were leveraged in PDA, where we demonstrate that radiotherapy potently enhanced the effect of GOT1 inhibition on tumor growth. Taken together, these results illustrate the role of tissue type in dictating metabolic dependencies and provide new insights for targeting metabolism to treat PDA.
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This is an abstract of a preprint hosted on an independent third party site. It has not been peer reviewed but is currently under consideration at Nature Communications.