title: Molecular profiling reveals primary mesothelioma cell lines recapitulate human disease.
abstract: Malignant mesothelioma (MM) is an aggressive, fatal tumor strongly associated with asbestos exposure. There is an urgent need to improve MM patient outcomes and this requires functionally validated pre-clinical models. Mesothelioma-derived cell lines provide an essential and relatively robust tool and remain among the most widely used systems for candidate drug evaluation. Although a number of cell lines are commercially available, a detailed comparison of these commercial lines with freshly derived primary tumor cells to validate their suitability as pre-clinical models is lacking. To address this, patient-derived primary mesothelioma cell lines were established and characterized using complementary multidisciplinary approaches and bioinformatic analysis. Clinical markers of mesothelioma, transcriptional and metabolic profiles, as well as the status of p53 and the tumor suppressor genes CDKN2A and NF2, were examined in primary cell lines and in two widely used commercial lines. Expression of MM-associated markers, as well as the status of CDKN2A, NF2, the 'gatekeeper' in MM development, and their products demonstrated that primary cell lines are more representative of the tumor close to its native state and show a degree of molecular diversity, thus capturing the disease heterogeneity in a patient cohort. Molecular profiling revealed a significantly different transcriptome and marked metabolic shift towards a greater glycolytic phenotype in commercial compared with primary cell lines. Our results highlight that multiple, appropriately characterised, patient-derived tumor cell lines are required to enable concurrent evaluation of molecular profiles versus drug response. Furthermore, application of this approach to other difficult-to-treat tumors would generate improved cellular models for pre-clinical evaluation of novel targeted therapies.
authors.affiliation: MRC Toxicology Unit, University of Leicester, Leicester, UK.
authors.forename: T
authors.initials: T
authors.lastname: Chernova
authors.affiliation: MRC Toxicology Unit, University of Leicester, Leicester, UK.
authors.forename: X M
authors.initials: XM
authors.lastname: Sun
authors.affiliation: MRC Toxicology Unit, University of Leicester, Leicester, UK.
authors.forename: I R
authors.initials: IR
authors.lastname: Powley
authors.affiliation: MRC Toxicology Unit, University of Leicester, Leicester, UK.
authors.forename: S
authors.initials: S
authors.lastname: Galavotti
authors.affiliation: MRC Toxicology Unit, University of Leicester, Leicester, UK.
authors.forename: S
authors.initials: S
authors.lastname: Grosso
authors.affiliation: MRC Toxicology Unit, University of Leicester, Leicester, UK.
authors.forename: F A
authors.initials: FA
authors.lastname: Murphy
authors.affiliation: MRC Toxicology Unit, University of Leicester, Leicester, UK.
authors.forename: G J
authors.initials: GJ
authors.lastname: Miles
authors.affiliation: UHL NHS Trust, Leicester Royal Infirmary, Leicester, UK.
authors.forename: L
authors.initials: L
authors.lastname: Cresswell
authors.affiliation: MRC Toxicology Unit, University of Leicester, Leicester, UK.
authors.forename: A V
authors.initials: AV
authors.lastname: Antonov
authors.affiliation: UHL NHS Trust, Glenfield Hospital, Leicester, UK.
authors.forename: J
authors.initials: J
authors.lastname: Bennett
authors.affiliation: UHL NHS Trust, Glenfield Hospital, Leicester, UK.
authors.forename: A
authors.initials: A
authors.lastname: Nakas
authors.affiliation: MRC Toxicology Unit, University of Leicester, Leicester, UK.
authors.forename: D
authors.initials: D
authors.lastname: Dinsdale
authors.affiliation: MRC Toxicology Unit, University of Leicester, Leicester, UK.
authors.forename: K
authors.initials: K
authors.lastname: Cain
authors.affiliation: MRC Toxicology Unit, University of Leicester, Leicester, UK.
authors.forename: M
authors.initials: M
authors.lastname: Bushell
authors.affiliation: MRC Toxicology Unit, University of Leicester, Leicester, UK.
authors.forename: A E
authors.initials: AE
authors.lastname: Willis
authors.affiliation: MRC Toxicology Unit, University of Leicester, Leicester, UK.
authors.forename: M
authors.initials: M
authors.lastname: MacFarlane
mesh_terms: D000368:Aged; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D050763:Cyclin-Dependent Kinase Inhibitor p18 / Q000235:genetics / Q000378:metabolism; D005260:Female; D042822:Genomic Instability; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008654:Mesothelioma / Q000378:metabolism* / Q000473:pathology; D000086002:Mesothelioma, Malignant; D055442:Metabolome; D008875:Middle Aged; D025581:Neurofibromin 2 / Q000235:genetics / Q000378:metabolism; D010101:Oxygen Consumption; D025341:Principal Component Analysis; D020080:Tandem Repeat Sequences; D059467:Transcriptome; D014407:Tumor Cells, Cultured; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C000614131:CDKN2A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050763:Cyclin-Dependent Kinase Inhibitor p18; D025581:Neurofibromin 2; C495901:TP53 protein, human; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53