The pathogenesis of mesothelioma is driven by a dysregulated translatome

Our plain-English summary of The pathogenesis of mesothelioma is driven by a dysregulated translatome, by S. Grosso, A. Marini, K. Gyuraszova, et al (Nature Communications, 2021).

The study

• Authors: S. Grosso, A. Marini, K. Gyuraszova, J.V. Voorde, A. Sfakianos, G.D. Garland, A.R. Tenor, R. Mordue, T. Chernova, N. Morone, M. Sereno, C.P. Smith, L. Officer, P. Farahmand, C. Rooney, D. Sumpton, M. Das, A. Teodósio, C. Ficken, M.G. Martin, R.V. Spriggs, X.M. Sun, M. Bushell, O.J. Sansom, D. Murphy, M. MacFarlane, J.P.C. Le Quesne, A.E. Willis
• Journal: Nature Communications
• Published: 2021;12(1):4920
• Cited by: 28 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

© 2021. The Author(s).

In plain English

This laboratory study examined how malignant pleural mesothelioma (MpM) cells make proteins from messenger RNA (mRNA). The authors compared eight cell lines grown from patients' tumours with mesothelial cells from healthy donors. In the tumour cells, 1665 genes' mRNAs were significantly more associated with the protein-making machinery and 282 were less associated. The increases mainly involved mitochondria and protein synthesis. The tumour cells made protein faster, had fragmented mitochondria and used more oxygen. In surgical tumour samples from 272 patients, the growth marker Ki67 was positively associated with several of these proteins, and high Ki67 was linked to worse survival. Drugs that block both mTORC1 and mTORC2 reduced protein synthesis and growth in tumour cells and in tumour pieces from two patients. Rapamycin, which blocks mTORC1 alone, did not significantly change overall protein synthesis. In genetically engineered mice given long fibre amosite asbestos by injection into the pleural space, the drug combination AZD2014 plus AZD8186 significantly extended survival compared with mice given an inactive vehicle (9 mice per group). The authors concluded that the data strongly suggest that targeting mTORC1 and 2 would restrict tumour cell growth in patients with MpM.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study: patient-derived tumour cell lines compared with healthy mesothelial cells, a tissue microarray of archival surgical tumour samples, drug treatment of fresh tumour explants, and a drug treatment experiment in a genetically engineered, asbestos-injected mouse model
• Who was studied: Eight primary cell lines derived from patients with MpM (Meso 3T, 7T, 8T, 9T, 12T, 13T, 14T, 17T). Controls were peritoneal mesothelial cells from a single healthy donor (NM) or a pool of four donors (NMS). The tissue microarray used 272 archival surgical tumour samples from patients who had surgery for primary malignant pleural mesothelioma at University Hospitals of Leicester from 2003 to 2014. Explants came from two patients (8 explants). The mouse experiment used 18 mice (9 treated, 9 vehicle).
• Exposure: In the mouse model, mice lacking Cdkn2a and carrying floxed Nf2 and Tp53 alleles received Lenti-Cre and, 10 days later, a single intrapleural injection of 25 μg long fibre amosite asbestos. From day 60 they were treated daily with AZD8186 (50 mg/kg twice daily) plus AZD2014 (15 mg/kg once daily) or vehicle. In cells and explants the drugs tested were Torin1, AZD2014, rapamycin, hippuristanol, 4EGI-1 and EFT508. The study did not measure asbestos exposure in the patients.
• Main results:
  • In the 8 MpM-derived cell lines compared with controls, 1665 genes were significantly upregulated in polysome association and 282 were downregulated.
  • The most enriched groups among the highly translated mRNAs in the MpM-derived cell lines related to mitochondria and protein synthesis.
  • MpM-derived tumour cells had greatly elevated global levels of mRNA translation compared with healthy mesothelial cells.
  • Mitochondria in control cells formed an elongated network, whereas in MpM cells they were fragmented. Basal and maximum oxygen consumption were raised in MpM-derived cell lines relative to the control.
  • In two mesothelioma-derived cell lines (Meso 7T and 8T) compared with NMS controls, there was a twofold increase in intracellular malate.
  • In the 272-patient tissue microarray, patients with high Ki67 expression had significantly worse overall survival (log-rank p = 0.025). Ki67 was significantly positively associated with phospho-rpS6 (Spearman coefficient 0.274), eIF4A1 (0.26), ATP5A (0.182) and SDH (0.116).
  • In MpM cells, rapamycin (mTORC1 inhibition alone) had no significant effect on global protein synthesis. Dual mTORC1 and 2 inhibition with Torin1 significantly reduced protein synthesis and cell growth but did not induce apoptosis.
  • In tumour explants (two patients, 8 explants) treated with mTORC1 and 2 inhibitors, protein synthesis decreased, along with decreases in SDH, ATP5A and Ki67 staining.
  • In the asbestos-induced mouse model, AZD2014 plus AZD8186 (n = 9 mice) significantly extended survival compared with vehicle control (n = 9 mice). No median survival times are given in the text.
• The authors' conclusion: The authors concluded that the data strongly suggest that inhibiting translation and energy production by targeting mTORC1 and 2 would restrict tumour cell growth in patients with MpM and provide a viable treatment option.
• Limitations the authors state:
  • The authors note that the increase in free amino acids after treatment is likely also influenced by autophagy, which they did not explore further.
  • The authors note that eIF4A likely reduces cell growth through additional mechanisms that are still being studied.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Mesothelioma, Malignant Mesothelioma, Asbestos Exposure, Polysome, Disease Progression.

Related studies

• 4EGI-1 represses cap-dependent translation and regulates genome-wide translation in malignant pleural mesothelioma — A. De, B.A. Jacobson, et al. (2018)
• Integrated Analysis of Dysregulated ncRNA and mRNA Expression Profiles in Humans Exposed to Carbon Nanotubes — A.A. Shvedova, N. Yanamala, et al. (2016)
• Long-Fiber Carbon Nanotubes Replicate Asbestos-Induced Mesothelioma with Disruption of the Tumor Suppressor Gene Cdkn2a (Ink4a/Arf) — T. Chernova, F.A. Murphy, et al. (2017)
• Small-molecule inhibition of oncogenic eukaryotic protein translation in mesothelioma cells — E.Z. Chen, B.A. Jacobson, et al. (2014)
• Expression of Clara cell secretory protein in the lungs of rats exposed to silicon carbide whisker in vivo — Y. Morimoto, L. Ding, et al. (2003)
• Combined Inhibition of NEDD8-Activating Enzyme and mTOR Suppresses NF2 Loss-Driven Tumorigenesis — J. Cooper, Q. Xu, et al. (2017)

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