Understanding how low UPF1 expression leads to drug resistance in bladder cancers
Not stated
- Funding
- Self-Funded PhD Students Only
- Application deadline
- Year-round applications
About the project
About the Project Metastatic urothelial carcinoma carries one of the poorest prognoses of any solid tumour: 5-year survival for metastatic disease is only around 5.5%, despite an initial response rate to first-line platinum-based chemotherapy of up to 55%. Median overall survival following standard treatment remains approximately 14 months, and while immune checkpoint inhibitors have improved outcomes for a subset of patients, only a minority of patients with metastatic disease respond durably to these agents. This stark divergence, with some patients surviving for many years, whilst others dying within months of diagnosis on comparable treatment, indicates that fundamental biological differences between tumours determine treatment resistance and lethal outcome. What drives this divergence remains largely unknown. We have access to a unique tissue resource comprising 270 metastatic bladder cancer samples, deliberately selected to span this clinical divide: patients who survived beyond 5 years following treatment, and patients who died within 6 - 12 months of diagnosis. This resource offers an opportunity to directly compare the microenvironmental features of tumours across these 2 cohorts. This project will: Apply spatial transcriptomic profiling across the full tissue cohort, generating spatially resolved gene expression data covering DNA damage repair, tumour hypoxia, immune infiltration, and other pathways implicated in treatment resistance. Identify molecular and spatial signatures that distinguish long-term survivors from patients with rapidly lethal disease, correlating findings with clinical and treatment history. Validate candidate resistance pathways using orthogonal molecular biology approaches, including multiplex tissue imaging and functional assays using in vitro bladder cancer models, to establish mechanistic causality and identify potential therapeutic targets. This is an exciting opportunity to work across clinical oncology and molecular cancer biology, using a large, clinically annotated patient cohort to address a question of direct relevance to how metastatic bladder cancer patients are treated and stratified. Proposed start date: March 2026 / October 2027 Entry Requirements: Candidates must have a first or upper second class honours degree with significant research experience. How to apply: Please complete a University Postgraduate Research Application form available here: http://www.shef.ac.uk/postgraduate/research/apply Please clearly state the prospective main supervisor in the respective box and select School of Medicine & Population Health as the department. Enquiries: Interested candidates should in the first instance contact Dr Hannah Bolland ( h.bolland@sheffield.ac.uk ) or Professor Syed Hussain ( syed.hussain@sheffield.ac.uk ).