(Fellowship) Investigating the trigger for fibroblast senescence in colorectal cancer: a novel

Bowel cancer is the second most common cause of cancer death in the UK and most deaths occur when cancer spreads to other parts of the body. Although there have been marked improvements in life expectancy following bowel cancer in the past 20 years, there is still scope for better detection, risk-stratification and treatment. One way to achieve this is to precisely understand differences between normal and cancerous bowel at a molecular level. If certain molecules are more or less abundant in cancer, then these differences can be utilised to develop diagnostic tests, predict the likelihood of cancer coming back after treatment and design more effective drugs, which destroy cancer cells with less collateral damage. An important concept to understand is that cancer is more than cancer cells. A tumour consists of cancer cells, supporting cells and structural molecules. These components interact to allow the tumour to expand and spread. One type of supporting cell, known as a fibroblast, is well known for regulating the architecture of a tumour. Fibroblasts are strongly linked with tumour development, growth and spread. As fibroblasts age, it is though that they produce different molecules, which accelerate tumour growth. There are several proposed mechanisms for fibroblast aging but the trigger is unclear. Our laboratory is interested in how cancer cells affect supporting cells and what influence this has on the tumour as a whole. Our initial experiments show that certain bowel cancer cells transmit messages to fibroblasts in tiny packages called vesicles. The effect of this is to bring about aging in the fibroblasts, which we know leads to cancer progression. One of the transmitted messages has been identified as a molecule called miR-143. The aim of this project is to find out how bowel cancer cells cause fibroblasts to age. We think that: (i) cancer cells transmit miR-143 to fibroblasts in vesicles; (ii) miR-143 causes fibroblasts to age; (iii) miR-143-related aging causes fibroblasts to release particular molecules which make the tumour grow and spread. To investigate this, miR-143 levels will be artificially altered in fibroblasts and aging will be assessed. Molecules produced by fibroblasts with artificially high miR-143 will be identified. These molecules will be fed back to cancer cells to see if they cause increased growth and greater spread. This work has the potential to identify the trigger for fibroblast aging in bowel cancer. With this information, it may be possible to identify patients who are at higher risk of death so that they can have more intensive treatment. Equally, it makes it possible to design a drug which can prevent fibroblast aging, potentially reducing tumour growth and spread. Our research group has a good balance of clinicians and scientists and the unique blend of skills to make this project feasible. As a surgical trainee, I bring a perspective which ensures that my research is focused on areas of clinical need so that any findings can be translated efficiently into beneficial outcomes for patients.