Dr Johan Vande Voorde, Dr Kevin Myant, Prof Konstantinos Gerasimidis, Dr Shahida Din, Prof Owen Sansom
Project Description
Inflammatory bowel disease (IBD) is a risk factor for colorectal cancer (CRC). The development of IBD is considered a result of pathological interactions between immune-mediated, environmental, and microbial factors. IBD is associated with gut microbiota ‘dysbiosis’, a community imbalance characterised by expansion of opportunistic pathogens. Dysbiosis can disrupt the mucosal barrier causing chronic inflammation and carcinogenesis. Further, changes in microbiota alter the metabolic potential of the community which can affect the intestinal metabolic environment. Our preliminary data using germ-free animals show that an intact microbiome is also required to maintain circulating metabolites that may be of relevance for signalling or host immunity.
Here, we aim to understand the role of the microbiome in IBD-CRC, hypothesizing that inflammation-induced dysbiosis modifies microbial metabolite abundance and influences disease progression. We generated a novel mouse model of IBD-CRC which accurately recapitulates the histopathological features of the human disease. In this model, cancer arises on the background of defined oncogenic mutations and repeated cycles of colonic inflammation allowing the contribution of both genetic, environmental, and microbial factors to be assessed. We will utilise this model to study gut microbiome composition during disease progression, and subsequent effects on local/circulating metabolites. Functional studies and intervention strategies will be designed to understand the role of pathogenic metabolic and microbial alterations in disease development/severity.
Aim 1. Define alterations in intestinal microbiota in IBD-associated CRC
Faecal matter has been collected from VilCreERT2 Trp53fl/fl KrasG12D/+ mice prior to, and after transgene induction, and during repeated periods of DSS-induced colitis. We will study alterations in faecal microbiota community representation using 16S amplicon sequencing. We found a significant degree of variability in disease presentation between animals, which we will correlate with individual microbial alterations. Findings will be validated at two independent in vivo facilities (University of Edinburgh & CRUK Scotland Institute) to define conserved changes. The impact of selected species on disease development/progression can be tested using in vivo colonization studies for which collaborations to perform experiments in a gnotobiotic setting are established if required.
Aim 2. Define alterations in bacterial metabolites in IBD-associated CRC
Longitudinal blood and faecal samples have been collected from VilCreERT2 Trp53fl/fl KrasG12D/+ mice as these undergo colitis-associated cancer development. We will employ (un)targeted metabolomics to analyse changes in faecal/circulating metabolites. These will be correlated with pathological presentation and gut microbiome constitution of the same animals (Aim1) to identify disease-relevant metabolites. Individual metabolites will be studied using in vitro approaches (e.g. effect on immune cell activation, organoid growth, microbial physiology, etc.). Selected hits will be taken forward for validation using in vivo metabolite supplementation studies.
Aim 3. Modulate the microbiome to improve outcome of IBD-associated CRC
VilCreERT2 Trp53fl/fl KrasG12D/+ mice will be treated with broad-spectrum antibiotics to test the impact of microbial depletion on disease progression. Specific intervention strategies will be designed based on data from Aims 1&2. These can include class-specific depletion using antibiotics, regulation of microbial composition/function using dietary intervention, or modulation of disease relevant metabolic pathways.
Training offered
The successful candidate will be trained in preclinical models of IBD and IBD-associated colorectal cancer. This includes complex genetically-engineered mouse models using Cre/lox technology. State-of-the-art metabolomics will be employed to decipher the contribution of the microbiome to intestinal and circulating metabolites during disease progression. This will include both targeted and untargeted approaches using the liquid chromatography-mass spectrometry and gas chromatography-mass spectrometry platforms available at the CRUK Beatson Institute. 16S rRNA sequencing will be employed to study alterations in intestinal bacterial communities and to identify microbial organisms with relevance to this work. In vitro assays using intestinal organoids will be employed to further elucidate the effects of bacterial metabolites on cell growth and behaviour. Mechanistic studies will be performed using standard molecular biology techniques (e.g. qPCR, western blotting, etc.).
We anticipate that the majority of the experimental work associated with this project will be performed in the Vande Voorde and Myant labs, but the successful candidate will benefit from the close interaction with Din, Gerasimidis, and Sansom teams. Furthermore, our group has the necessary experience for future human clinical validation of potential modifiable targets in the highly relevant patient cohorts at risk of IBD associated colorectal cancer.
For further information on the project or informal enquiries, please contact Dr Johan Vande Voorde, This email address is being protected from spambots. You need JavaScript enabled to view it.
To place an application, please visit this site at the University of Glasgow.
When submitting your application please upload the completed recruitment form.
Lab Websites
Dr Johan Vande Voorde
Dr Kevin Myant
Prof Konstantinos Gerasimidis
Prof Owen Sansom
Papers of interest
1. Vande Voorde J.*, Steven R.T., Najumudeen A.K., Ford C.A., Dexter A., Gonzalez-Fernandez A., Nikula C.J., Xiang Y., Ford L., Maneta Stavrakaki S., Gilroy K., Zeiger L.B., Pennel K., Hatthakarnkul P., Elia E.A., Nasif A., Murta T., Manoli E., Mason S., Gillespie M., Lannagan T.R.M., Vlahov N., Ridgway R.A., Nixon C., Raven A., Mills M., Athineos D., Kanellos G., Nourse C., Gay D.M., Hughes M., Burton A., Yan B., Sellers K., Wu V., De Ridder K., Shokry E., Huerta Uribe A., Clark W., Clark G., Kirschner K., Thienpont B., Li V.S.W., Maddocks O.D.K., Barry S.T., Goodwin R.J.A., Kinross J., Edwards J., Yuneva M.O., Sumpton D., Takats Z., Campbell A.D., Bunch J., Sansom O.J.* (2020) Metabolic profiling stratifies colorectal cancer, and reveals adenosylhomocysteinase as a therapeutic target. Nature Metabolism 5(8):1303-1318. *: corresponding authors.
2. Hall, A.E., Pohl, S.Ö., Cammareri, P., Aitken, S., Younger, N.T., Raponi, M., Billard, C.V., Carrancio, A.B., Bastem, A., Freile, P., Haward, F., Adams, I.R., Caceres, J.F., Preyzner, P., von Kriegsheim, A., Dunlop, M.G., Din, F.V., Myant, K.B. (2022) RNA splicing is a key mediator of tumour cell plasticity and a therapeutic vulnerability in colorectal cancer. Nature Communications. 19;13(1):2791.
3. Zafeiropoulou, K., Nichols, B., Mackinder, M., Biskou, O., Rizou, E., Karanikolou, A., Clark, C., Buchanan, E., Cardigan, T., Duncan, H., Wands, D., Russell, J., Hnasen, R., Russel, R.K., McGrogan, P., Edwards, C., Ijaz, U.Z, Gerasimidis, K. (2020) Alterations in Intestinal Microbiota of Children With Celiac Disease at the Time of Diagnosis and on a Gluten-free Diet. Gastroenterology 159:2039-2051.
4. Porter, R.J., Arends, M.J., Churchhouse, A.M.D., Din, S. (2021) Inflammatory bowel disease-associated colorectal cancer: translational risks from mechanisms to medicines. Journal of Chron’s and Colitis 15(12):2131-2141.
5. Najumudeen, A.K., Ceteci, F., Fey, S.K., Hamm, G., Steven, R.T., Hall, H., Nikula, C.J., Dexter, A., Murta, T., Race, A.M., Sumpton, D., Vlahov, N., Gay, D.M., Knight, J.R.P., Jackstadt, R., Leach, J.D.G., Ridgway, R.A., Johnson, E.R., Nixon, C., Hedley, A., Gilroy, K., Clark, W., Malla, S.B., Dunne, P.D., Rodriguez-Blanco, G., Critchlow, S.E., Mrowinska, A., Malviya, G., Solovyev, D., Brown, G., Lewis, D.Y., Mackay, G.M., Strathdee, D., Tardito, S., Gottlieb, E., CRUK Rosetta Grand Challenge Consortium, Takats, Z., Barry, S.T., Goodwin, R.J.A., Bunch, J., Bushell, M., Campbell, A.D., Sansom, O.J. (2021) The amino acid transporter SLC7A5 is required for efficient growth of KRAS-mutant colorectal cancer. Nature Genetics 53(1):16-26.