Cell Death Differ. 2016 Feb 19. doi: 10.1038/cdd.2015.165. [Epub ahead of print]

Molecular profiling reveals primary mesothelioma cell lines recapitulate human disease.

Chernova T1, Sun XM1, Powley IR1, Galavotti S1, Grosso S1, Murphy FA1, Miles GJ1, Cresswell L2, Antonov AV1, Bennett J3, Nakas A3, Dinsdale D1, Cain K1,Bushell M1, Willis AE1, MacFarlane M1.

Author information

• 1MRC Toxicology Unit, University of Leicester, Leicester, UK.
• 2UHL NHS Trust, Leicester Royal Infirmary, Leicester, UK.
• 3UHL NHS Trust, Glenfield Hospital, Leicester, UK.

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.