PhD project

Supervisor: Bass Hassan

One of the major challenges in cancer is how to selectively disrupt the cancer cell yet leave all normal functioning cells intact. The two main approaches are either exploit the genomic variant expression and MHC presentation of ‘non-self’ antigens or to identify variant dependent synthetic (synergistic) cancer cell lethality (dependencies). The aim of this project is to evaluate latter mechanisms of synthetic lethality in cancers of mesenchyme (sarcoma) that are characterised by aneuploidy and copy number variation. The laboratory has already completed several genome-wide CRISPR screens to identify context dependent candidate hits linked to TP53, NF1 and SUZ12.  Here, the student will evaluate molecular mechanisms of identified lethality target genes in relation to genomic context. Through extensive analysis of NGS sequencing and CRISPR drop out screens using multiplex gRNAs detailed mechanistic evaluation in sarcoma cells that may require additional methodology, for example combining structural genomic manipulation, evaluation of ecDNA amplification, gene expression and proteomic analysis combined with molecular cell and structural biology. Importantly, genomic copy number context, paralogs and the epigenome are all factors that are likely to influence the context of synthetic lethality and the prospect for functional targets for therapeutic agents. 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 laboratory with day-to-day post-doctoral supervision, gain first-hand experience in cancer biology, CRISPR based genome engineering, cancer genomics, cancer bioinformatics, molecular and structural biology, pre-clinical target validation and an understanding of basic science linked to clinical translation.

Keywords:

• Cancer, Sarcoma, Synthetic Lethality, Oncology, Genetics, Molecular Biology, CRISPR Library Screening, Bioinformatics, Chromatin