Engineering of human artificial chromosomes to decipher the mechanisms of chromosome instability-driven prostate cancer progression

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Prostate cancer (PCa) is the most commonly diagnosed cancer in the UK and Europe, and responsible for close to 110,000 male deaths annually. Up to 20% of PCa cases present hallmarks of genomic instability characterized by chromosomal amplifications in the right arm of chromosome 8 (Chr.8q) -commonly associated with treatment resistance and poor survival rates. The Chr.8q region harbours the c-Myc oncogene whose copy gain was thought to be a strong candidate to explain the poor prognosis.To note, c-Myc copy number alterations (CNA) in minimally gained 8q regions can involve the co-amplification of up to 40-50 other genes, some acting as oncogenes involved in prostate, ovarian and breast cancer.4 Given the genetic complexity of chromosomal gains, the functional consequences of these amplified loci remain unknown due to the lack of cell models that can recapitulate the full genetic sequence, and order of that sequence, for use in cell models, both in vitro and in vivo. Therefore, this proposal aims to implement and engineer human artificial chromosomes (HAC) to reproduce the observed genetic aberrations in patients to decipher the mechanisms of chromosome amplifications-driven increased metastatic capability of cancer cells. This project has the potential to create a brand-new gold standard approach to model, characterise and screen for new drug candidate against genomic instability-related diseases.Objectives: Objective 1. Implementation of human artificial chromosomes mimicking Chr-8a amplification;Objective 2. Computational analysis, assembly and incorporation of the Chr-8q amplified regions;Objective 3. Deciphering the impact of copy gain on cancer progression