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.

This PhD project at the University of Oxford investigates the impact of autoantibodies (AAbs) on cancer, focusing on their potential as biomarkers and their role in tumorigenesis. Autoantibodies are produced by the immune system and recognize self-antigens; while present in all individuals, their excessive production is associated with pathological conditions such as autoimmune diseases and cancer. Recent research has linked increased AAb production to patient responses to checkpoint inhibitor blockade (CBI) immunotherapies, including anti-PD1 and anti-PDL1 treatments. AAbs against cytokines and chemokines have been shown to predict disease severity, suggesting their utility as biomarkers and indicators of immune fitness. The project aims to systematically profile AAbs in cohorts ranging from healthy individuals to patients with precancerous conditions, operable cancers, and metastatic cancers, both before and after immunotherapy. State-of-the-art technologies such as yeast display and protein array will be used to generate cancer AAb 'fingerprints.' Unique AAbs will be cloned from human peripheral blood mononuclear cells (PBMCs) and assayed in vitro using molecular and cellular biology techniques, including live cell imaging. Building on findings from the LUD2015-005 trial of oesophageal adenocarcinoma patients, the project will expand the investigation to broader cancer and healthy cohorts. The goal is to identify AAbs of interest and functionally validate their role in tumorigenesis, laying the groundwork for their use as biomarkers for early detection, treatment stratification, or novel therapies. Key approaches include co-culture techniques, antibody-antigen interaction studies, organoid technology to explore tumor-immune cell interactions, and single-cell sequencing to dissect cellular responses. Additional assays such as antibody-dependent cell-mediated cytotoxicity (ADCC) will be performed. The project is supervised by Professor Xin Lu, Director of the Ludwig Institute for Cancer Research, and Professor Lynn Dustin, an expert in autoimmunity. Students will receive training in cell and molecular biology techniques, single-cell genomics, and organoid technology, benefiting from the expertise and resources at both the Ludwig Institute and Kennedy Institute. Opportunities for integration with Oxford's scientific and clinical communities, as well as national and international conferences, are provided. The Ludwig training and career development programme includes regular oral presentations, journal clubs, and skills development in writing, data management, and public engagement. Funding is available through Ludwig studentships, which provide four years of support including a tax-free stipend (£23,000 per annum) and university fees at home and international rates. Applicants must apply via the University of Oxford application 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. The application deadline is April 9, 2026.