Targeting the Intestinal Stem Cell Niche through Energy and Metabolism Signalling, via mTOR, for Colorectal Cancer Chemoprevention using aspirin and metformin

A 3-year PhD Studentship with Dr Farhat Din at the Institute of Molecular Medicine at the University of Edinburgh. Colorectal cancer (CRC), a common cause of cancer death, is largely preventable through modifying lifestyle related risk factors. CRC risk factors including diabetes, obesity, and metabolic syndrome, highlight strong links with metabolism and diet. The key metabolic regulator mTOR modulates the intestinal stem cell response to nutrients to maintain homeostasis. mTOR is progressively abnormal in CRC. There is powerful rationale to capitalise on known preventive agents to realign deranged metabolism and recalibrate mutation and transformation vulnerable stem cells. Robust epidemiological data indicates that aspirin and metformin greatly reduce CRC risk.

The host lab has previously shown that aspirin activates AMPK (negative mTOR regulator) and inhibits mTOR in CRC cells and mouse and patient intestine (1). Data from the group also showed that 33% of patients on aspirin develop CRC (2).The absence of biomarkers of response prevent their use as mainstream chemopreventives. Data from the lab show that aspirin can rescue cancer stem cell phenotypes. The project will test the hypothesis that aspirin and metformin recalibrate aberrant stem cell metabolism, driven by excessive nutrients, to prevent pre-neoplastic phenotypes. The research involves study of cellular signalling pathways that may be modulated by chemopreventive agents to prevent colorectal cancer in human and in vitro studies.

The project is aimed at investigating the effects of these agents on nutrient and metabolism signalling and stem cells in colorectal neoplasia. The role will include cell culture, human and mouse tissue sample preparation and organoid culture, analysis using cell and molecular biological techniques. Immunohistochemistry of mouse and human intestinal material will also be involved. All experiments will be clearly outlined and supervised to allow progression of the project.

This project is an exciting opportunity to study CRC chemoprevention in a translational lab with potential to study significant findings in in-vivo treated tissue samples. The group is part of the Edinburgh University Cancer Research Centre and the Institute of Genetic and Molecular Medicine, which comprises a substantial grouping of the largest MRC Unit in the UK, the University of Edinburgh Molecular Medicine Centre and the Cancer Research UK Cancer Centre.

Applicants should send a covering letter, stating why they are interested in the project, along with an up-to-date CV, which includes two academic referees to [Email Address Removed] by 10 June 2017.