Grant: CIHR Fellowship

Squamous cell carcinoma of the skin (SCC) is the second most common cancer worldwide and affects > 20,000 Canadians each year. SCCs are aggressive and although most cases can be excised by surgery, patients with weak immune systems or a history of sun exposure can develop many SCCs, threatening life. Elucidating the cellular changes that occur in SCC progression is needed to improve SCC therapies which are limited and often ineffective. SCCs arise from the surface tissue of the skin, called epidermis. The epidermis has a remarkable ability to renew itself every 30 days, and also repair wounds. This is made possible by special long-lived cells called stem cells. To enhance the production of desired self-renewal and survival proteins, healthy stem cells suppress a group of small inhibitory RNAs, known as the let-7 microRNAs. When present, these microRNAs can bind to and block the translation of specific messenger RNAs (their "targets"). By blocking let-7 miRNAs, stem cells can survive. Interestingly, let-7 microRNAs are often suppressed in human cancers, and my preliminary analysis suggests that this is true for skin stem cells and their cancers. What proteins are elevated when let-7 miRNAs are suppressed, whether this differs in stem cells and cancer, and whether targets are uniform across tissues and cancers remains unknown. I plan to tackle these important problems. Specifically, I will first use bioinformatics to predict all possible target messenger RNAs for let-7 miRNAs, and using the Fuchs lab databases, identify which are dysregulated in SCCs. Then, I will exploit a powerful new technology developed in the Fuchs laboratory to rapidly screen through this cohort of putative targets and reveal those that drive malignant progression. By contrasting my data to human cancer databases, I will complete my objective, and in so doing, I hope to unveil new therapeutic targets for cancer in general and SCC in particular.