Taming the Hippo in cancer through Proteogenomics

Malignant Pleural Mesothelioma (MPM) is a cancer occurring in the peritoneal cavity of the lungs, developing in the mesothelial cells of the pleura. It is a rare but aggressive cancer with relatively low survival rate of 12 - 24 months following diagnosis and ineffectiveness of current treatments leading to poor prognosis for the disease. This mainly due to poor understanding of the disease, which is why it is important to investigate the molecular mechanisms responsible for its pathogenesis. With recent advancements in technologies for omics techniques, it has become possible to probe deeper into the genetic and molecular basis of the disease. Recent exome sequencing studies have identified significant mutations in genes for proteins associated with the Hippo pathway, which makes it a good target for a deeper investigation. For this, the project aims to use a powerful omics technique called proteogenomics, which integrates data generated from proteomics, genomics and transcriptomics to understand the direct effect of genetic mutations on the proteome and the transcriptome. Using this technique, the effect of the loss of function mutations in the hippo pathway will be directly compared to that of other significantly mutated genes to uncover their mechanism of involvement in mesothelioma. Their phenotype will further be tested experimentally in isogenic cells lines, allowing selection of biomarkers to be used in stratification of patients and neo-antigens for drug discovery, thereby personalising diagnostics and treatments for MPM patients.