Journal Article

The pathogenesis of mesothelioma is driven by a dysregulated translatome

Martin, Maria Guerra, Mordue, Ryan, Teodósio, Ana, Garland, Gavin D., MacFarlane, Marion, Willis, Anne E., Officer, Leah, Morone, Nobu, Sereno, Marco, Das, Madhumita, Sumpton, David, Ficken, Catherine, Bushell, Martin, Farahmand, Pooyeh, Smith, Claire P., Sun, Xiao-Ming, Marini, Alberto, Le Quesne, John P. C., Spriggs, Ruth V., Voorde, Johan Vande, Grosso, Stefano, Rooney, Claire, Sfakianos, Aristeidis, Sansom, Owen J., Murphy, Daniel, Tenor, Angela Rubio, Gyuraszova, Katarina, Chernova, Tanya

2021

Overview

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. Treating malignant pleural mesothelioma (MpM) is challenging due to a lack of druggable genes, but other molecular features could be clinically useful. Here the authors profile mRNA translation dysregulation in MpM cell lines using polysome profiling, and identify mTORC1 and 2 as potential pharmacological targets.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/1 / 13/105 / 13/106 / 13/109 / 14 / 14/19 / 14/28 / 38 / 38/47 / 38/88 / 631/67/1641 / 631/80/304 / Animal models / Animals / Asbestos / Biosynthesis / Cell growth / Humanities and Social Sciences / Humans / Mechanistic Target of Rapamycin Complex 1 - antagonists & inhibitors / Mechanistic Target of Rapamycin Complex 1 - metabolism / Mechanistic Target of Rapamycin Complex 2 - antagonists & inhibitors / Mechanistic Target of Rapamycin Complex 2 - metabolism / Mesothelioma / Mesothelioma, Malignant - chemically induced / Mesothelioma, Malignant - genetics / Mesothelioma, Malignant - metabolism / Mice / Mice, Inbred C57BL / Mice, Knockout / Mitochondria / Mitochondria - genetics / Mitochondria - metabolism / Morphology / mRNA / multidisciplinary / Naphthyridines - pharmacology / Non-pharmacological intervention / Oncogenes - genetics / Oxygen consumption / Pathogenesis / Patients / Pharmacology / Polyribosomes - drug effects / Polyribosomes - metabolism / Protein biosynthesis / Protein Biosynthesis - drug effects / Protein Biosynthesis - genetics / Proteins / RNA, Messenger - genetics / RNA, Messenger - metabolism / Science / Science (multidisciplinary) / Translation / Tumor Cells, Cultured / Tumor suppressor genes / Tumors