Simon Buczacki

This PhD project at the University of Oxford investigates the remarkable rarity of cancer in the small intestine compared to other parts of the gastrointestinal (GI) tract, such as the oesophagus, stomach, and colon. Despite high cancer incidence in most GI regions, the small intestine experiences cancer rates approximately 20 times lower than the large intestine. The project aims to uncover the molecular and cellular mechanisms that protect the small intestine from tumor formation, a key challenge in cancer biology. Recent advances have identified genetic alterations contributing to GI cancer initiation, progression, and treatment resistance, but the factors preventing small intestine tumors remain largely unknown. The hypothesis is that epithelial cells from different GI regions possess varying levels of cell plasticity—a process crucial for cancer initiation—regulated by external exposures and epigenetic modulators. The project will explore how epigenetic modulators alter cell plasticity and whether epithelial cells from different GI regions respond differently to these modulators. To quantitatively measure changes in cell plasticity, the research leverages the state-of-the-art SAM (Shape, Appearance and Motion)/SPOT (SAM Phenotype Observation Tool) technology, recently developed by the group (Zhou et al., 2025). This live-cell imaging platform enables detailed morphodynamic analysis and phenotype-genotype coupling in 3D organoids. The project will utilize high-content live-cell imaging of human organoids, applying genetic and chemical compound screening focused on libraries that modulate epigenetic and transcriptional regulation. Identified hits from the screening will be validated and functionally characterized in vitro using 3D organoid cultures, either alone or in co-culture with immune and stroma cells. Further characterization will employ single cell RNA-seq and spatial transcriptomics to assess effects on cell plasticity and epigenetic/transcriptional regulation of cell fate. If time allows, in vivo validation will be conducted in preclinical models. The project is supervised by Professor Xin Lu, Director of the Ludwig Institute for Cancer Research, and co-supervised by Professor Simon Buczacki, a clinician scientist and colon cancer surgeon. The student will benefit from expertise and technologies at both the Ludwig Institute and the Nuffield Department of Surgical Sciences, as well as opportunities to engage with Oxford’s scientific and clinical communities and attend national and international conferences. Training includes cell and molecular biology techniques, single cell genomics, and organoid methods, alongside career development activities such as journal clubs, oral presentations, and skills workshops. Funding is provided through Ludwig studentships, covering a four-year tax-free stipend (£23,000 per annum) and university fees at home and international rates. Applicants must apply via the University of Oxford system for a DPhil in Clinical Medicine, submitting a personal statement and ensuring referees are prepared to provide references by the deadline. Contacting the supervisor to discuss fit is recommended. For further information, see the project and course web pages.