The pathogenesis of mesothelioma is driven by a dysregulated translatome

Stefano Grosso, Alberto Marini, Katarina Gyuraszova, Johan Vande Voorde, Aristeidis Sfakianos, Gavin D. Garland, Angela Rubio Tenor, Ryan Mordue, Tanya Chernova, Nobu Morone, Marco Sereno, Claire P. Smith, Leah Officer, Pooyeh Farahmand, Claire Rooney, David Sumpton, Madhumita Das, Ana Teodósio, Catherine Ficken, Maria Guerra Martin, Ruth V. Spriggs, Xiao-Ming Sun, Martin Bushell, Owen J. Sansom, Daniel Murphy (), Marion MacFarlane (), John P. C. Quesne () and Anne E. Willis ()
Additional contact information
Stefano Grosso: University of Cambridge
Alberto Marini: University of Cambridge
Katarina Gyuraszova: University of Glasgow
Johan Vande Voorde: Cancer Research UK Beatson Institute, Garscube Estate
Aristeidis Sfakianos: University of Cambridge
Gavin D. Garland: University of Cambridge
Angela Rubio Tenor: University of Cambridge
Ryan Mordue: University of Cambridge
Tanya Chernova: University of Cambridge
Nobu Morone: University of Cambridge
Marco Sereno: University of Cambridge
Claire P. Smith: University of Cambridge
Leah Officer: University of Cambridge
Pooyeh Farahmand: University of Glasgow
Claire Rooney: University of Glasgow
David Sumpton: Cancer Research UK Beatson Institute, Garscube Estate
Madhumita Das: University of Cambridge
Ana Teodósio: University of Cambridge
Catherine Ficken: University of Cambridge
Maria Guerra Martin: University of Cambridge
Ruth V. Spriggs: University of Cambridge
Xiao-Ming Sun: University of Cambridge
Martin Bushell: University of Glasgow
Owen J. Sansom: University of Glasgow
Daniel Murphy: University of Glasgow
Marion MacFarlane: University of Cambridge
John P. C. Quesne: University of Cambridge
Anne E. Willis: University of Cambridge

Nature Communications, 2021, vol. 12, issue 1, 1-17

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-25173-7

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