Aberrant post-translational control: The cancer connection
Dysregulated post-transcriptional control of gene expression makes a major contribution to carcinogenesis and we have demonstrated that altered mRNA translation initiation in Malignant pleural mesothelioma (MpM) an aggressive, invariably fatal tumour that is causally linked with asbestos exposure, is mediated up increased signalling through mTOR1. We have now identified changes in the proteins that were translationally upregulated and carried out orthogonal organic phase separation (OOPS)2 in primary cell lines derived from patients with MpM and found global alterations in RNA binding proteins (RBPs). We identified over 500 RBPs that have altered RNA binding and/or expression that are involved in a wide range of functions including splicing, cell cycle control and metabolism. Interestingly, many of these proteins have been previously found to be associated with tumour aggressiveness, including HuR/ELAV1 and our mechanistic data demonstrates how these RBPs promote cell growth. In addition, we have explored the impact of inhibition of the elongation stage of protein synthesis in MpM and show that this also contributes to accelerated cell growth. Finally, we have used a range of inhibitors to target mRNA translation, RBPs or the downstream pathways in MpM and show that these can provide new therapeutic avenues for this incurable disease.
1. Grosso S et al (2021) Nature Commun. 2021; 12: 4920.
2. Rayner M. L. (2019) Nat Biotechnol. 2019l 37: 169–178.
3. Rubio et al (2025) in preparation
4. Sfakianos et al (2025), Nature Commun. (in press)