RT Journal Article
SR Electronic
T1 Tissue of Origin Dictates GOT1 Dependence and Confers Synthetic Lethality to Radiotherapy
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 714196
DO 10.1101/714196
A1 Barbara S. Nelson
A1 Lin Lin
A1 Daniel M. Kremer
A1 Cristovão M. Sousa
A1 Cecilia Cotta-Ramusino
A1 Amy Myers
A1 Johanna Ramos
A1 Tina Gao
A1 Ilya Kovalenko
A1 Kari Wilder-Romans
A1 Joseph Dresser
A1 Mary Davis
A1 Ho-Joon Lee
A1 Zeribe C. Nwosu
A1 Scott Campit
A1 Oksana Mashadova
A1 Brandon N. Nicolay
A1 Zachary P. Tolstyka
A1 Christopher J. Halbrook
A1 Sriram Chandrasekaran
A1 John M. Asara
A1 Howard C. Crawford
A1 Lewis C. Cantley
A1 Alec C. Kimmelman
A1 Daniel R. Wahl
A1 Costas A. Lyssiotis
YR 2019
UL http://biorxiv.org/content/early/2019/07/25/714196.abstract
AB 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.