Fleming MRC Fellowship MR/L017172/1 Tensin regulation of tumour cell movement: a link between metabolism and motility

Cancer cells generate their energy mostly through a process known as glycolysis. In normal cells this only usually occurs when oxygen supply is limited, but cancer cells use this pathway preferentially, even when oxygen is present (aerobic glycolysis). There is some debate as to the advantage this confers to tumour cells, since it is an inefficient pathway for generating energy, but it is thought that it provides tumour cells with a growth advantage by generating molecules required for cell division. The potential for cancer cell metabolism to impact on patient management has been shown through the use of positron emission tomography (PET) for the detection of tumours. However, it is becoming clear that rather than being simply a marker for detection, a tumour cell's glycolytic nature may alter cell function. Recently we have found that aerobic glycolysis in cancer cells promotes cell invasion, and this may link altered tumour metabolism with tumour spread. Motility in cancer cells in particular has great significance, as it is required for cancer cells to spread either into local tissues (invasion) or other parts of the body (metastasis). Movement through tissues requires cancer cells to interact with the extracellular matrix (ECM), and this is regulated through specialised integrin receptors on the cell surface. We are interested in a molecule called Tensin, which serves to link integrins to scaffolding (structural) proteins inside the cell. Far from acting solely as a structural support, we have found that Tensins play a role in cancer cell movement, and that expression of these molecules can be regulated by cell metabolism; aerobic glycolysis in cancer cells results in the activation of a metabolic sensor (CtBP2 protein), which controls the level of Tensin. In turn, this affects the way in which cancer cells adhere and/or move on the ECM and provides a novel link between metabolism and motility. Through our work exploring the relationship between tumour metabolism, Tensins and extracellular matrix interactions, we hope to identify key targets in the metabolic sensing and signalling pathways, furthering our understanding of the mechanisms regulating tumour cell invasion and metastasis, and possibly enabling the identification of new diagnostic and therapeutic targets. I am a 3rd year otolaryngology (ENT)/head & neck surgical trainee, with a strong desire to use molecular biology techniques to revolutionise our approach to cancer. This research is being performed in a UK centre of excellence at the University of Southampton, and involves the combined research expertise of two Internationally recognised leading groups in these disciplines. The methods and techniques that I will master during this research include a variety of cell-based assays and will be key not only for my future academic career, but will also enable the development of key research skills within the surgical community. I am passionate to drive this collaboration between science and surgery forward.