Identification of new therapeutic targets: Down-modulation of inhibitory-SMADs as a route to CRC prevention
Primary Supervisor: Dr Ian Tomlinson
The bone morphogenetic protein (BMP) pathway plays an important role in adult tissue homoeostasis, particularly in the large bowel. BMP ligands are released by fibroblastic mesenchymal cells and signal to the epithelium to restrain stem and progenitor cell phenotypes and allow cellular differentiation. Secreted BMP antagonists bind and inactivate BMPs, preventing the loss of stem and progenitor cells.
Through our own and others’ work, it has been demonstrated that genetic variation in most of the major BMP pathway components is associated with colorectal cancer (CRC) predisposition and, with few exceptions, these effects are very specific to CRC. Increasing BMP signaling acts to restrain colorectal tumour formation.
Two critical BMP pathway components are SMAD6 and SMAD7, which are so-called inhibitory-SMADs (I-SMADs). I-SMADs operate downstream of the BMP receptors in epithelial cells to inhibit BMP signalling, predominantly by repressing transcription of the ID genes, which are BMP effectors. In humans, inherited variation in expression of SMAD6 and SMAD7 predisposes to CRC (lower expression = lower risk).
This project will address the importance of the Smad6 and Smad7 inhibitor proteins in bowel homeostasis and their role in CRC development in murine models. The data obtained from this research project will show the consequences in the normal intestine of reducing or losing I-SMAD activity, and will underpin future experiments to target I-SMADs as a means of CRC prevention in humans.
• Develop skills in tissue culture and screens of anti-cancer drugs and small molecules
• Develop skills the analysis of human and mouse tissues using multiple molecular methods
• Work within a larger host laboratory programme to understand BMP pathway signalling and its critical role in the development of bowel cancer
Law, P.J., Timofeeva, M., Fernandez-Rozadilla, C., Broderick, P., Studd, J., Fernandez-Tajes, J., Farrington, S., Svinti, V., Palles, C., Orlando, G. and Sud, A., 2019. Association analyses identify 31 new risk loci for colorectal cancer susceptibility. Nature communications, 10(1), pp.1-15.
Broderick, P., Carvajal-Carmona, L., Pittman, A.M., Webb, E., Howarth, K., Rowan, A., Lubbe, S., Spain, S., Sullivan, K., Fielding, S. and Jaeger, E., 2007. A genome-wide association study shows that common alleles of SMAD7 influence colorectal cancer risk. Nature genetics, 39(11), pp.1315-1317.