Quantifying and modelling stress-related dysregulation of mRNA translation in primary human tumour tissue

There is an urgent need for improved treatments and therapies for advanced stage lung cancer, and one promising strategy is to directly target hallmark phenotypes mediated by translational dysregulation. Stress-related dysregulation of mRNA translation occurs as a result of the phosphorylation of the a-subunit of eukaryotic initiation factor 2 (eIF2). While stress-related dysregulation of mRNA translation has been well-characterised in cell-based models, there is limited understanding of the effects of phosphorylated eIF2a (p-eIF2a) in primary human tumour tissue, or of whether targeting translational dysregulation is a viable strategy. This project aims to investigate the extent to which stress-related dysregulation of mRNA translation occurs in human lung adenocarcinoma and if it contributes to the virulence of the disease. To address this,  immunohistochemistry and in situ hybridisation methods were used to quantify markers of the integrated stress response pathway and translational control in 1025 primary human lung adenocarcinoma patient cases, statistical analyses were performed to investigate the associations between translational dysregulation and patient outcome, tumour hallmarks, and between various elements of the stress signalling pathway. It was found that the phosphorylation of eIF2a occurs in areas of hypoxic stress, despite the lack of known mechanism to mediate this. The phosphorylation of eIF2a was found to be strongly associated with aggressive tumour hallmarks, namely invasiveness, metastasis, and cellular proliferation, as well as poor clinical outcomes. Furthermore, the lethal phenotype associated with p-eIF2a was not significantly linked either to the previously characterised downstream mediator, ATF4, or by the abundance of subunits of eIF2B, the functional binding partner of eIF2a. Stress signalling through eIF2, likely mediated by regional hypoxia, is predictive of poor prognosis in primary lung adenocarcinoma, and that targeting mRNA translational dysregulation through the phosphorylation of eIF2a may be clinically valuable in preventing tumour invasiveness and metastasis.