Kennedy Trust Prize Studentships
The interleukin 23 axis in colorectal cancer
Inflammation and immunity are critical modulators of colorectal cancer (CRC) progression. While anti-tumour immunity in humans is generally associated with favourable prognosis, inflammation driven by the IL-23/Th17 cell axis is related to poor outcome. Cytokines produced downstream of IL-23 promote CRC development in animal models. Notably, microbe driven IL-23 induces IL-22, which acts directly on intestinal epithelial cells to promote growth and survival. Importantly, IL-22 mediates CRC progression in animal models of both colitis-associated and sporadic (mutation-driven) cancer and also promotes malignant behaviour in human CRC cell lines. Though attractive as a possible therapeutic target for CRC, direct evidence supporting a tumourigenic role for the IL-23 pathway in humans is lacking. Work in the Powrie lab has recently identified a novel synergy between IL-22 and a key oncogenic driving mutation, KRAS, which confers poor prognosis in human CRC.
To assess the relevance of the IL-23 pathway in human CRC and its tractability as a therapeutic target, we use novel ex vivo culture systems to conduct functional experiments in primary, patient-derived tissue. Three-dimensional organoids are grown from tumour biopsies and normal adjacent mucosa, while infiltrating immune cells and surrounding stromal cells are concomitantly expanded. Co-culture experiments with each of the component parts (epithelial, immune, stromal) of the complex tumour microenvironment enable interrogation of specific inter- and intra-cellular signaling pathways.
This project will make use of primary human CRC tissue to understand the precise mechanism of synergy between IL-22 and KRAS, to characterize the immune milieu in tumours of different molecular subtypes, and to understand the reciprocal signaling between the immune and epithelial compartments. Key targets identified and validated in the human system, may be probed in murine CRC models used in the lab, to pinpoint specific mechanisms. Insights gleaned into the role of the IL-23 pathway and its downstream effectors (ie. IL-22) in this ex vivo human system serve as direct proof of concept work for moving toward therapeutic modulation of the IL-23 pathway in the clinic.
Students interested in this project will benefit from close integration and collaboration with a multidisciplinary team including scientists, gastroenterologists, oncologists, research nurses, and biobankers and close ties with the Translational Gastroenterology Unit at Oxford. Students will be based at the Kennedy Institute of Rheumatology, where they will benefit from state-of-the-art molecular biology, flow cytometry, and microscopy infrastructure. This project is ideally suited to a student with a strong molecular biology background and an interest in both cancer biology and immunology. This project will be primarily wet-lab based, but the student will have an opportunity to develop their computational skill-set to analyse data generated from RNA-seq and proteomics experiments.
The Kennedy Institute is a world-renowned research centre and is housed in a brand new state-of-the-art research facility. It is ideally situated on the Old Road Campus next to the Ludwig Insitute for Cancer Research, the Wellcome Trust Centre for Human Genetics, and the Big Data Institute. Training will be provided across the range of cell, molecular, and bioinformatics techniques. A core curriculum of 20 lectures will be taken in the first term of year 1 to provide a solid foundation in musculoskeletal sciences, immunology and data analysis. Students will attend weekly departmental meetings, journal clubs, and will be expected to attend seminars within the department and those relevant in the wider University. Subject-specific training will be received through our group's weekly lab meetings. Students will also attend external scientific conferences where they will be expected to present the research findings.
- Kirchberger S, Royston DJ, Boulard O, et al: Innate lymphoid cells sustain colon cancer through production of interleukin-22 in a mouse model. J Exp Med 210:917–931, 2013
- West NR, McCuaig S, Franchini F, et al: Emerging cytokine networks in colorectal cancer. Nat Rev Immunol 15:615–629, 2015
Inflammation in Cancer, Mucosal Immunology.