title: Synthetic dosage lethality in the human metabolic network is highly predictive of tumor growth and cancer patient survival.
abstract: Synthetic dosage lethality (SDL) denotes a genetic interaction between two genes whereby the underexpression of gene A combined with the overexpression of gene B is lethal. SDLs offer a promising way to kill cancer cells by inhibiting the activity of SDL partners of activated oncogenes in tumors, which are often difficult to target directly. As experimental genome-wide SDL screens are still scarce, here we introduce a network-level computational modeling framework that quantitatively predicts human SDLs in metabolism. For each enzyme pair (A, B) we systematically knock out the flux through A combined with a stepwise flux increase through B and search for pairs that reduce cellular growth more than when either enzyme is perturbed individually. The predictive signal of the emerging network of 12,000 SDLs is demonstrated in five different ways. (i) It can be successfully used to predict gene essentiality in shRNA cancer cell line screens. Moving to clinical tumors, we show that (ii) SDLs are significantly underrepresented in tumors. Furthermore, breast cancer tumors with SDLs active (iii) have smaller sizes and (iv) result in increased patient survival, indicating that activation of SDLs increases cancer vulnerability. Finally, (v) patient survival improves when multiple SDLs are present, pointing to a cumulative effect. This study lays the basis for quantitative identification of cancer SDLs in a model-based mechanistic manner. The approach presented can be used to identify SDLs in species and cell types in which "omics" data necessary for data-driven identification are missing.
authors.affiliation: Institute for Computing and Information Science, Radboud University, Nijmegen, 6525 EC Nijmegen, The Netherlands; Centre for Molecular and Biomolecular Informatics, Radboud University Medical Center, 6525 GA, Nijmegen, The Netherlands; Centre for Systems Biology and Bioenergetics, Radboud University Medical Center, 6525 GA, Nijmegen, The Netherlands;
authors.forename: Wout
authors.initials: W
authors.lastname: Megchelenbrink
authors.affiliation: Center for Bioinformatics and Computational Biology, Department of Computer Science, University of Maryland, College Park, MD 20742;
authors.forename: Rotem
authors.initials: R
authors.lastname: Katzir
authors.affiliation: Centre for Molecular and Biomolecular Informatics, Radboud University Medical Center, 6525 GA, Nijmegen, The Netherlands;
authors.forename: Xiaowen
authors.initials: X
authors.lastname: Lu
authors.affiliation: Center for Bioinformatics and Computational Biology, Department of Computer Science, University of Maryland, College Park, MD 20742; School of Computer Science and School of Medicine, Tel-Aviv University, Tel Aviv, Israel, 69978; ruppin@post.tau.ac.il richard.notebaart@radboudumc.nl.
authors.forename: Eytan
authors.initials: E
authors.lastname: Ruppin
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, 6525 GA, Nijmegen, The Netherlands ruppin@post.tau.ac.il richard.notebaart@radboudumc.nl.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Notebaart
mesh_terms: D003198:Computer Simulation; D018628:Gene Dosage / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D005804:Genes, Lethal / Q000235:genetics*; D016147:Genes, Tumor Suppressor; D006801:Humans; D053858:Metabolic Networks and Pathways / Q000235:genetics / Q000502:physiology*; D008957:Models, Genetic; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism; D009857:Oncogenes / Q000235:genetics; D049490:Systems Biology / Q000379:methods*
keywords: cancer; genetic interactions; human metabolism; synthetic dosage lethality; systems biology