Mechanism evaluation of lethality dependencies in cancers of mesenchyme.

About the project

About the Project A major challenge in cancer is how to selectively and permanently disrupt the cancer cell yet leave normal functioning cells intact. The two main approaches are either to exploit the cancer specific genomic nucleotide and structural variants for lethality dependencies or to modify the immune system to destroy cancer cells via cell surface antigens and MHC presentation of ‘non-self’ antigens. The aim of this project is to evaluate former mechanisms of synthetic lethality dependencies in cancers of mesenchyme (sarcoma) that are characterised by aneuploidy and selected copy number variation. The laboratory has already completed several genome-wide enAsCas12a CRISPR screens to identify context dependent candidate dependency genes linked to disruption of TP53 , 17p , CDKN2A/B , NF1 and SUZ12/EED . Here, the student will extend this analysis to evaluate molecular mechanisms of dependencies from the identified lethality target genes in relation to pathway and genomic context. The project will focus of candidate pathway and gene dependencies from one of the screens and will involve molecular, bioinformatic and structural analysis. Additional methodology may include structural genomic manipulation, gain-of-function screens evaluation, gene expression, RNA translation and proteomic analysis. Importantly, genomic context, paralogs and the epigenome are all factors that are also likely to influence the context of synthetic lethality and the prospect for functional targets for translational application. Ultimately, mechanistic validation of targets will be incorporated into improved personalised diagnostics and selective therapeutics for sarcoma. The student will join an established multi-disciplinary basic and translational laboratory with day-to-day post-doctoral supervision, gain first-hand experience in sarcoma biology and pre-clinical target validation.

Research areas