RT Journal Article
SR Electronic
T1 Personalized Genome-Scale Metabolic Models Identify Targets of Redox Metabolism in Radiation-Resistant Tumors
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.04.07.029694
DO 10.1101/2020.04.07.029694
A1 Joshua E. Lewis
A1 Tom E. Forshaw
A1 David A. Boothman
A1 Cristina M. Furdui
A1 Melissa L. Kemp
YR 2020
UL http://biorxiv.org/content/early/2020/04/08/2020.04.07.029694.abstract
AB Redox cofactor production is integral towards antioxidant generation, clearance of reactive oxygen species, and overall tumor response to ionizing radiation treatment. To identify systems-level alterations in redox metabolism which confer resistance to radiation therapy, we developed a bioinformatics pipeline for integrating multi-omics data into personalized genome-scale flux balance analysis models of 716 radiation-sensitive and 199 radiation-resistant tumors. These models collectively predicted that radiation-resistant tumors reroute metabolic flux to increase mitochondrial NADPH stores and ROS scavenging. Simulated genome-wide knockout screens agreed with experimental siRNA gene knockdowns in matched radiation-sensitive and –resistant cancer cell lines, revealing gene targets involved in mitochondrial NADPH production, central carbon metabolism, and folate metabolism that allow for selective inhibition of glutathione production and H2O2 clearance in radiation-resistant cancers. This systems approach represents a significant advancement in developing quantitative genome-scale models of redox metabolism and identifying personalized metabolic targets for improving radiation sensitivity in individual cancer patients.