The pathogenesis of mesothelioma is driven by a dysregulated translatome

Marini, A. et al. (2021) The pathogenesis of mesothelioma is driven by a dysregulated translatome. Nature Communications, 12, 4920. (doi: 10.1038/s41467-021-25173-7)

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Abstract

Malignant mesothelioma (MpM) is an aggressive, invariably fatal tumour that is causally linked with asbestos exposure. The disease primarily results from loss of tumour suppressor gene function and there are no ‘druggable’ driver oncogenes associated with MpM. To identify opportunities for management of this disease we have carried out polysome profiling to define the MpM translatome. We show that in MpM there is a selective increase in the translation of mRNAs encoding proteins required for ribosome assembly and mitochondrial biogenesis. This results in an enhanced rate of mRNA translation, abnormal mitochondrial morphology and oxygen consumption, and a reprogramming of metabolic outputs. These alterations delimit the cellular capacity for protein biosynthesis, accelerate growth and drive disease progression. Importantly, we show that inhibition of mRNA translation, particularly through combined pharmacological targeting of mTORC1 and 2, reverses these changes and inhibits malignant cell growth in vitro and in ex-vivo tumour tissue from patients with end-stage disease. Critically, we show that these pharmacological interventions prolong survival in animal models of asbestos-induced mesothelioma, providing the basis for a targeted, viable therapeutic option for patients with this incurable disease.

Item Type:Articles
Additional Information:The work was funded by MRC programme core funding to A.E.W., M.M.F. and JLQ (5TR00, 5TR019 and MCA/600). British Lung Foundation grants CSOBLFRG16-2 and MKMRGPG18 to D.J.M., K.G., J.V.dV., P.F., C.R., D.S., O.J.S., M.B. were supported by Cancer Research UK core funding to the Beatson Institute (A17196) and core funding to O.J.S. (A21139) and M.B. (A29252). A.E.W. is a member of the Health Protection Research Unit in Chemical and Radiation Threats and Hazards, a partnership between Public Health England and Imperial College London which is funded by the National Institute for Health Research (NIHR).
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Murphy, Professor Daniel and ROONEY, Dr CLAIRE and Le Quesne, Professor John and Sansom, Professor Owen and Bushell, Professor Martin and Gyuraszova, Dr Katarina and Farahmand, Dr Pooyeh
Authors: Marini, A., Grosso, S., Gyuraszova, K., Voorde, J. V., Sfakianos, A., Garland, G. D., Tenor, A. R., Mordue, R., Chernova, T., Morone, N., Sereno, M., Smith, C. P., Officer, L., Farahmand, P., Rooney, C., Sumpton, D., Das, M., Teodósio, A., Ficken, C., Martin, M. G., Spriggs, R. V., Sun, X.-M., Bushell, M., Sansom, O. J., Murphy, D., MacFarlane, M., Le Quesne, J. P.C., and Willis, A. E.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Nature Communications
Publisher:Nature Research
ISSN:2041-1723
ISSN (Online):2041-1723
Copyright Holders:Copyright © 2021 The Authors
First Published:First published in Nature Communications 12:4920
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
173568Pre-clinical evaluation of pan-ERBB inhibition to treat KRAS mutant NSCLCDaniel MurphyBritish Lung Foundation (BLF)CSOBLFRG16-2Institute of Cancer Sciences