Bristow-MB-PhD-001- The role of chromosomal gains in defining clinical aggression in prostate cancer

Closing date: 03/02/2023

MB-PhD Project: The role of chromosomal gains in defining clinical aggression in prostate cancer

Lead Supervisor: Prof. Robert Bristow
Email: robert.bristow@manchester.ac.uk | Executive Assistantcaroline.stone@manchester.ac.uk
Co-Supervisors: Prof. David WedgeProf. Patrick CaiDr Pedro Oliveira

Initial Intercalation Deadline: 12 December 2022
Interviews: Tuesday 7 March 2023
Final Deadline for Permission to Intercalate (UoM Programmes): 26 May 2023

MB-PhD Start Date: September 2023
Project Keywords: 
Chromosomal instability, bioengineering, prostate cancer
Research Opportunity:
Intercalated PhD, leading to the award of PhD and MBChB

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Cancer Research UK Manchester Centre | Bristow-MB-PhD-001- The role of chromosomal gains in defining clinical aggression in prostate cancer

Applications for this project are now open. Candidates must contact prospective supervisor/s ahead of submitting an application. See the MB-PhD programme page for details of how to apply. 

 

Project Outline

Aggressive cancer phenotypes result from the imbalance of one or more dosage-sensitive genes in a particular chromosomal segment. An exemplar is the chromosomal gain of the right arm of 8q (Chr.8q) in prostate, ovarian and breast cancer; this gain is associated with poor clinical outcome.

 

Up to 20% of prostate cancer (PCa) cases present with Chr. 8q, which harbours the c-Myc oncogene with co-amplification of up to 30-40 other genes. This usually is detected by sequencing techniques based on bulk DNA from a tumour section, but whether sub-clones exist at a cellular level showing cell to cell heterogeneity for gains is not known. This project will use molecular pathology approaches (in situ FISH, chromosomal instability assays, genomics and spatial transcriptomics) to understand the intra-prostatic cell heterogeneity of chromosomal gains using spatial ‘omics on tumour foci within individual patient’s prostate glands removed at surgery. The validation of DNA and RNA endpoints will lever whole genome/RNA sequencing and outcome data within the Pan Prostate Cancer Group (international consortium with over 1200 PCa annotated genomes).  We hypothesise that chromosomal gains are focal within the prostate cancers in which co-amplified genes work together to drive genetic instability with subsequent clonal selection and adaption into aggressive phenotypes. A better understanding of cell to cell heterogeneity could drive new therapies against aggressive subclones.

 

Functional genomic studies to validate pathology findings is an option using prostate epithelial cells (PrEC) transfected with engineered Human Artificial mini-Chromosomes (HACs). These HAC-Chr. 8q cells would mirror the genetics of Chr. 8q gains (e.g. a mini-chromosome, with c-Myc and other co-amplified genes) to inform upon genetic instability, mutations and cell growth autonomy.  The work will be completed primarily in the laboratory of Prof. Robert Bristow at the CRUK Manchester Institute (in vitro models; DCS-FBMH) in collaboration with Prof. Patrick Cai (HAC systems; FSE-Manchester Institute of Biotechnology), Prof. David Wedge (cancer genomics; DCS-FBMH) and Dr. Pedro Oliveira (Christie pathology).

 

About the Bristow Lab

“As a clinician scientist, projects and mentees that reflect an interest in wanting to improve patient care are welcome approaches in my translational lab. Open/honest communication and clear expectations between mentor and mentee are central to a successful graduate training experience. I am strongly committed to a vibrant, safe, collegial and supportive research environment where all researchers from diverse perspectives and backgrounds are valued; I expect that the mentee has the same ethos. Research in my lab will be of the highest research integrity. There is zero tolerance bullying or harassment consistent with confidential hotline availability for mentees and CRUK, Christie and UoM guidelines”.

 

Supervisory Style 

“In my practice with the starting PhD students-there are intensive 1:1 sessions with me in the first 8 weeks around the background knowledge and clinical translation aspects of the study. Dr. Pedro Oliveira will review the pathological aspects within the Christie path lab over this period and has extensive and successful experiences with APEP students. We will arrange clinical theatre visits to uplift this experience. The trainee will be aligned to selected work of a post-doc for technical training and will have a day-to-day technical advisor for support”.

 

Lab Culture

“My mentees are expected to develop their own research approach with my input. Mentees are expected to attend weekly lab meetings and journal clubs. During the week, I make myself available for 1:1 meetings, to discuss data or to have bespoke teaching sessions. I encourage my mentees to actively seek out appropriate internal and external collaborators for: best hypothesis generation; technologic advances to improve laboratory work; and, optimising the impact of their research”.

 

Publications and Existing Literature 

“Creativity, innovation and team science with collaborations are key features to developing a state-of-the-art research programme. When aligned with a mastering of the literature and critical appraisal, this approach leads to impactful peer-reviewed publication(s). Writing is a skill that requires consistent application and practice. Therefore, I strongly encourage my mentees to participate in grant proposal writing workshops and other mechanisms to improve their writing skills in order to prepare their initiatives in writing manuscripts or their thesis and authorship on manuscripts will always occur early in a research activity”.

 

Career Development

“Mentees will have the opportunity to write reviews and participate in the development of research proposals to support their scientific professional development. Mentees will also have the opportunity to attend a national/international meeting to present mature data; this increases their understanding of the field, critical appraisal of their work and networking”.

 

Work-Life Balance
“Work-life balance is very important as happiness and fulfilment in one reflects positively on the other”.

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