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.
Highlights
Malignant mesothelioma (MpM) is an aggressive, invariably fatal tumour that is causally linked with asbestos exposure
We show that in Malignant pleural Mesothelioma (MpM) there is a selective increase in the translation of mRNAs encoding proteins required for ribosome assembly and mitochondrial biogenesis, and this results in an enhanced global rate of mRNA translation, abnormal mitochondrial morphology and oxygen consumption, and reprogramming of metabolic outputs
We did not find any enrichment of internal ribosome entry sites[33], for the mRNAs encoding mitochondrial proteins, there was an enrichment of the TISU sequence in the 5′-UTR34
Summary
Malignant mesothelioma (MpM) is an aggressive, invariably fatal tumour that is causally linked with asbestos exposure. 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. We show that in MpM there is a selective increase in the translation of mRNAs encoding proteins required for ribosome assembly and mitochondrial biogenesis, and this results in an enhanced global rate of mRNA translation, abnormal mitochondrial morphology and oxygen consumption, and reprogramming of metabolic outputs. Inhibition of mRNA translation by pharmacological targeting of mTORC1 and 2, reverses these changes both in vitro and in ex vivo patient tumour tissue Such mTORC1 and 2 inhibition extends survival in animal models of asbestos-induced mesothelioma and taken together, our data suggest that targeting mRNA translation could provide a viable, alternative treatment route for this incurable disease
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