title: A Systems Oncology Approach Identifies NT5E as a Key Metabolic Regulator in Tumor Cells and Modulator of Platinum Sensitivity.
abstract: Altered metabolism in tumor cells is required for rapid proliferation but also can influence other phenotypes that affect clinical outcomes such as metastasis and sensitivity to chemotherapy. Here, a genome-wide association study (GWAS)-guided integration of NCI-60 transcriptome and metabolome data identified ecto-5'-nucleotidase (NT5E or CD73) as a major determinant of metabolic phenotypes in cancer cells. NT5E expression and associated metabolome variations were also correlated with sensitivity to several chemotherapeutics including platinum-based treatment. NT5E mRNA levels were observed to be elevated in cells upon in vitro and in vivo acquisition of platinum resistance in ovarian cancer cells, and specific targeting of NT5E increased tumor cell sensitivity to platinum. We observed that tumor NT5E levels were prognostic for outcomes in ovarian cancer and were elevated after treatment with platinum, supporting the translational relevance of our findings. In this work, we integrated and analyzed a plethora of public data, demonstating the merit of such a systems oncology approach for the discovery of novel players in cancer biology and therapy. We experimentally validated the main findings of the NT5E gene being involved in both intrinsic and acquired resistance to platinum-based drugs. We propose that the efficacy of conventional chemotherapy could be improved by NT5E inhibition and that NT5E expression may be a useful prognostic and predictive clinical biomarker.
authors.affiliation: Center for Proteomics and Metabolomics, Leiden University Medical Center (LUMC) , L4-Q, PO Box 9600, 2300RC Leiden, The Netherlands.
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Nevedomskaya
authors.affiliation: Division of Cancer, Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital , London W12 0NN, United Kingdom.|Division of Brain Sciences, Department of Medicine, Imperial College London , London W12 0NN, United Kingdom.
authors.forename: Richard
authors.initials: R
authors.lastname: Perryman
authors.affiliation: Division of Cancer, Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital , London W12 0NN, United Kingdom.
authors.forename: Shyam
authors.initials: S
authors.lastname: Solanki
authors.affiliation: Division of Brain Sciences, Department of Medicine, Imperial College London , London W12 0NN, United Kingdom.
authors.forename: Nelofer
authors.initials: N
authors.lastname: Syed
authors.affiliation: Center for Proteomics and Metabolomics, Leiden University Medical Center (LUMC) , L4-Q, PO Box 9600, 2300RC Leiden, The Netherlands.
authors.forename: Oleg A
authors.initials: OA
authors.lastname: Mayboroda
authors.affiliation: Division of Cancer, Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital , London W12 0NN, United Kingdom.
authors.forename: Hector C
authors.initials: HC
authors.lastname: Keun
mesh_terms: D015720:5'-Nucleotidase / Q000235:genetics / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016190:Carboplatin / Q000494:pharmacology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D005260:Female; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D009944:Organoplatinum Compounds / Q000494:pharmacology; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality; D016016:Proportional Hazards Models; D049490:Systems Biology; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D058851:GPI-Linked Proteins; D009944:Organoplatinum Compounds; C023359:iproplatin; D016190:Carboplatin; D015720:5'-Nucleotidase; C548241:NT5E protein, human; C049777:ormaplatin
keywords: O2PLS; cancer; chemometrics; chemotherapy; cisplatin resistance; data integration; metabonomics; transcriptomics