Harnessing the link between BRAF-mediated tumorigenesis and metabolism in cancer

Cancer is a genetic disease caused by mutations in the DNA. These mutations are heterogeneous and cancer of the same subtypes can present with different genetic makeups, which affect patients’ prognosis and response to therapy.

Nonetheless, factors other than genetics affect the risk of cancer onset and the severity of its progression. In particular, metabolism plays a major role in influencing tumour development. For example, diabetic and obese people have a higher probability of developing cancer than lean, healthy individuals, posing a serious health challenge as the occurrence of both metabolic disorders is increasing, especially in young individuals. The reasons for such predisposition remain unclear as it is unclear how metabolism interacts with the genetic changes that cause cancer, although we are now learning that this is a two-way interaction; on the one hand, the mutations that affect the DNA of cancer cells alter the metabolism of tumours and their ability to utilize nutrients, such as fat, sugar and protein; on the other hand, the impact of metabolic disorders on cancer incidence and progression is dictated by the genetic characteristics of the tumours and malignancies with a different genetic makeup responds differently to changes in individual metabolism.

The complex interaction between genes and metabolism is an intense area of research in our laboratory. We aim at unravelling the underling molecular mechanisms that govern this mutual dependence and use this information to develop life-style or pharmacological interventions that could help prevent cancer. We are currently working on a subset of colorectal cancers (CRCs) driven by a specific genetic alteration affecting the oncogene BRAF. BRAF mutation is essential for tumour development and is detected in 15-20% of all CRCs, which in practical terms means 6,000 to 8,000 newly diagnosed CRCs each year in the UK only. Several data, some of which have been generated by our laboratory, indicate that mutant BRAF leads to a reshaping of fat metabolism inside the cells, which is not observed in CRC that have genetic modification in genes other than BRAF. The research project proposed here aims at investigating how this metabolic alterations contribute to colorectal carcinogenesis and whether interference with metabolic reprogramming could be used as preventive or therapeutic anti-cancer approach.

The successful applicant will have access to the excellent core facilities within the Leicester Cancer Centre, which run a successful post-doctoral training programme. The appointed student will receive training from experienced scientists and senior colleagues. A wide varied of techniques will be employed, including cell culture, 3-dimension organoid culture, western blotting, real time PCR, in vivo management of genetically modified mouse models, immunohistochemistry, and metabolomics. The appointee will join a vibrant scientific environment driven to excellence and rigorously focused on translation research and patient benefit, and progress will be openly discussed in interdisciplinary meetings with supervisors and colleagues. Informal enquiries, including a CV, should be sent to Dr. Rufini ([Email Address Removed]) and Prof Brown ([Email Address Removed]).