Mechanistic exploration of genetic, environmental, and sex-specific risk factors to reduce colorectal cancer incidence and inequalities

Dr Vidya Rajasekaran, Prof Susan Farrington, University of Edinburgh & Dr Kathryn Pennel, University of Glasgow

Background

With significant disparities in incidence, progression, and outcomes influenced by genetic, environmental, and sex-specific factors, colorectal cancer remains one of the leading causes of cancer related mortality. The overarching goal of this project is to investigate mechanisms underlying this inequality and translational impact, by integrating clinical data and exploratory model research to identify actionable biomarkers and potential intervention strategies.
This project will leverage large patient-derived datasets and our established mouse models of CRC risk genes identified through GWAS, TWAS and sequencing studies. These models recapitulate key disease phenotypes, including sexually dimorphic tumour formation. These patient data (clinical meta, with access to tissue markers and spatial information) and model systems can be used to investigate the interplay between genetic predisposition, environmental/dietary/microbiome/ immune factors, and sex in CRC initiation, progression and survival, providing a number of interesting strands that can be developed by the successful student:
(A) Understanding sex specific mechanisms in CRC disparities:

Assess X-chromosome inactivation patterns and the contribution to sex-biased CRC incidence.
Characterize sex-specific differences in tumour microenvironment (primary tumour and adjacent normal colonic epithelium), using markers and spatial transcriptomics.
Investigate the role of sex hormones in tumour susceptibility through hormone depletion and replacement studies.

(B) Dietary/environmental/microbiome/immune influences on CRC risk:

Examine how dietary components, microbiome diversity, and immune interactions collectively shape CRC risk, identifying key modulators.
Determine the impact of genetic perturbations on tumour morphology, immune infiltration, and epithelial integrity, and explore dietary and microbial strategies to mitigate these effects.

Utilize multiple colorectal cancer datasets, including INCISE, adenoma cohort, the colorectal cancer GRI TMA cohort, colorectal cancer budding information, as well as emerging cohorts (Glasgow and Edinburgh) which include primary tumour, adjacent normal tissue, metastasis data, and therapy response information. This will allow for comprehensive analysis of CRC risk eQTL expression across different clinical contexts.

Integrate CRC risk eQTL expression with survival outcomes, tumour morphology, and immune phenotypes to refine CRC risk models and subtyping.
Profile eQTL expression across adenoma, Stages I-IV, metastasis, and normal colorectal epithelium to track molecular changes through the development of CRC.
Develop AI-based image analysis pipelines to integrate morphological and molecular data, leveraging available datasets to validate predictive models and improve precision in CRC diagnosis.

The CRC risk eQTLS being explored are:

SHROOM2 (Xp22): Plays a role in cytoskeletal organization and intestinal epithelial integrity.
FUT2 (19q13): Plays a role in mucosal glycosylation, immune regulation and microbiome composition.
POU2AF2 (11q23): Plays a role in abundance of tuft cells in colonic epithelium and affects tumorigenesis and survival in a well-studied CRC mouse model (ApcMin/+).

This project directly addresses cancer inequalities by integrating diverse risk factors such as genetics, sex-specific traits, and environmental influences, with a mechanistic and translational framework. With the use of cutting-edge in vivo, ex vivo, and computational approaches, this research aims to generate actionable insights for CRC risk stratification and targeted therapy strategies.

Skills/Techniques that will be gained

The Colorectal Cancer Theme includes the Edinburgh Colorectal Cancer group, a dynamic team of dedicated researchers including scientists, surgeons and bioinformaticians, working collaboratively to identify, understand and potentially influence CRC risk factors and progression. The successful candidate will receive specialized, comprehensive training in model systems including in-vivo (mouse models) and ex-vivo systems (organoids) (VRS/SMF/KP). This will encompass intestinal phenotyping, protein analysis, morphological profiling via cell painting, and genomic data generation and analysis (imaging, proteomics, transcriptomics), utilizing R, bioinformatics and AI methodologies (VRS/SMF/KP). This multidisciplinary training approach will equip the candidate with the skills and expertise needed for CRC genetics research, facilitated by exposure to diverse perspectives and methodologies within the team. The IGC (UoE), has numerous training opportunities including regular presentation platforms and professional development through the Institute of Academic Development. Available courses cover many areas of training support such as good research practices, data management, and scientific communication. Specific modules include designing effective presentation slides conference poster design, how to be an effective researcher, practical project management; presenting with ease – delivering presentations; research, researchers and the media, research ethics and integrity, and thesis writing. The University of Glasgow has equivalent training opportunities.

For further information on the project or informal enquiries, please contact Dr Vidya Rajasekaran, This email address is being protected from spambots. You need JavaScript enabled to view it.

When submitting your application please also upload the completed EDI recruitment form.

To place an application, please visit this site at the University of Edinburgh.