title: Flux balance analysis predicts essential genes in clear cell renal cell carcinoma metabolism.
abstract: Flux balance analysis is the only modelling approach that is capable of producing genome-wide predictions of gene essentiality that may aid to unveil metabolic liabilities in cancer. Nevertheless, a systemic validation of gene essentiality predictions by flux balance analysis is currently missing. Here, we critically evaluated the accuracy of flux balance analysis in two cancer types, clear cell renal cell carcinoma (ccRCC) and prostate adenocarcinoma, by comparison with large-scale experiments of gene essentiality in vitro. We found that in ccRCC, but not in prostate adenocarcinoma, flux balance analysis could predict essential metabolic genes beyond random expectation. Five of the identified metabolic genes, AGPAT6, GALT, GCLC, GSS, and RRM2B, were predicted to be dispensable in normal cell metabolism. Hence, targeting these genes may selectively prevent ccRCC growth. Based on our analysis, we discuss the benefits and limitations of flux balance analysis for gene essentiality predictions in cancer metabolism, and its use for exposing metabolic liabilities in ccRCC, whose emergent metabolic network enforces outstanding anabolic requirements for cellular proliferation.
authors.affiliation: Department of Biology and Biological Engineering, Chalmers University of Technology, Göteborg 41296, Sweden.
authors.forename: Francesco
authors.initials: F
authors.lastname: Gatto
authors.affiliation: Gene Expression Analysis Laboratory, Cancer Research UK London Research Institute, London WC2A 3LY, United Kingdom.
authors.forename: Heike
authors.initials: H
authors.lastname: Miess
authors.affiliation: 1] Gene Expression Analysis Laboratory, Cancer Research UK London Research Institute, London WC2A 3LY, United Kingdom [2] Theodor-Boveri-Institute, Biocenter, Am Hubland, 97074 Würzburg, Germany [3] Comprehensive Cancer Center Mainfranken, Josef-Schneider-Str.6, 97080 Würzburg, Germany.
authors.forename: Almut
authors.initials: A
authors.lastname: Schulze
authors.affiliation: Department of Biology and Biological Engineering, Chalmers University of Technology, Göteborg 41296, Sweden.
authors.forename: Jens
authors.initials: J
authors.lastname: Nielsen
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000378:metabolism*; D016923:Cell Death / Q000235:genetics; D002460:Cell Line; D016000:Cluster Analysis; D019295:Computational Biology; D003198:Computer Simulation; D004734:Energy Metabolism / Q000235:genetics*; D020869:Gene Expression Profiling / Q000379:methods; D055786:Gene Knockout Techniques; D020043:Genes, Essential; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results