The pathogenesis of mesothelioma is driven by a dysregulated translatome

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Malignant mesothelioma (MpM) is an aggressive cancer linked to asbestos exposure with limited treatment options.
• MpM lacks 'druggable' driver oncogenes, necessitating novel therapeutic targets.
• Understanding the molecular mechanisms driving MpM progression is crucial for developing effective treatments.

Purpose of the Study:

• To define the translatome of malignant mesothelioma (MpM) using polysome profiling.
• To identify key molecular alterations that drive MpM growth and progression.
• To evaluate the therapeutic potential of targeting mRNA translation in MpM.

Main Methods:

• Polysome profiling to analyze mRNA translation in MpM.
• Assessment of mitochondrial morphology and function.
• Pharmacological inhibition of mTORC1 and mTORC2 signaling pathways.
• In vitro and ex-vivo studies on MpM cells and patient tissues.
• In vivo studies using animal models of asbestos-induced mesothelioma.

Main Results:

• MpM exhibits increased translation of mRNAs involved in ribosome assembly and mitochondrial biogenesis.
• These translational changes lead to enhanced protein synthesis, altered mitochondrial function, and metabolic reprogramming.
• Inhibition of mRNA translation, particularly via combined mTORC1/2 targeting, reversed these alterations and reduced cancer cell growth.
• Pharmacological interventions prolonged survival in animal models of mesothelioma.

Conclusions:

• Selective mRNA translation is a key driver of malignant mesothelioma progression.
• Targeting mRNA translation, specifically through mTORC1/2 inhibition, represents a promising therapeutic strategy for MpM.
• These findings provide a basis for developing novel treatments for this incurable asbestos-related cancer.