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

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

The 2016 UK Roadmap Bio-design for the Bio-economy highlighted the substantial impact that synthetic biology can bring to the UK and global economies by developing: frontier science and technology; establishing a healthy innovation pipeline; a highly skilled workforce and an environment in which innovative science and businesses can thrive. Synthetic biology promises to transform the UK Bio-economy landscape, bringing bio-sustainable and affordable manufacturing routes to all industrial sectors and will ensure society can tackle many contemporary global Grand Challenges including: Sustainable Manufacturing, Environmental Sustainability Energy, Global Healthcare, and Urban Development. Whilst synthetic biology is burgeoning in the UK, we now need to build on the investments made and take a further lead in training next generation scientists to ensure sustained growth of a capable workforce to underpin the science base development and growth in an advanced UK bio-economy.
This training provided by this CDT will give students from diverse backgrounds a unique synthesis of computational, biomolecular and cellular engineering skills, a peer-to-peer and industrial network, and unique entrepreneurial insight. In so doing, it will address key EPSRC priority areas and Bioeconomy strategic priorities including: Next-generation therapeutics; Engineered biomaterials; Renewable alternatives for fuels, chemicals and other small molecules; Reliable, predictable, and scalable bioprocesses; Sustainable future; Lifelong health & wellbeing.
Advances created by our BioDesign Engineering approach will address major societal challenges by delivering new routes for chemical/pharma/materials manufacture through to sustainable energy, whilst providing clean growth and reductions in energy use, greenhouse gas emissions and carbon footprints. Increased industry awareness of bio-options with better civic understanding will drive end-user demand to create market pull for products. The CDT benefits from unrivalled existing academic-industry frameworks at the host institutions, which will provide direct links to industrial partners and a direct pathway to early economic and industrial impact.

This CDT will develop 80-100 next-generation scientists and technologists (via the funded cohort and wider integration of aligned students at the three institutions) as adept scientists and engineers, instilled with technical leadership, who as broadly trained individuals will fill key skills gaps and could be expected to impact internationally through leadership roles in the medium term. Importantly the CDT addresses key skill-gaps identified with industry, which are urgently required to create and support high value jobs that will enable the UK to compete in global markets. Commercialisation and entrepreneurship training will equip the next generation of visionaries and leaders needed to accelerate and support the creation of new innovative companies to exploit these new technologies and opportunities.

The UK government identified Synthetic Biology as one of the "Eight Great Technologies" that could be a key enabler to economic and societal development. This CDT will be at the forefront of research that will accelerate the clean growth agenda and the development of a resilient circular bioeconomy, and will align with key EPSRC prosperity outcomes including a productive, healthy and resilient nation. To foster wider societal impact, the CDT will expect all students to contribute to public outreach and engagement activities including: open days, schools visits, and science festival events: students will participate in an outreach programme, with special focus on widening participation.

This CDT will contribute to the development of industrial strategy through the Synthetic Biology Leadership Council (SBLC), Industrial Biotechnology Leadership Forum (IBLF), and wider Networks in Industrial Biotechnology and Bioenergy and Professional Institutes.