Targeting developmental cell states in melanoma

Over 16,000 people in the UK will be diagnosed with melanoma this year, and melanoma is now one of the most common cancers in young adults. In the past 15 years, new therapies have improved outcomes for many patients, but still almost half of people with metastatic melanoma die from the disease. We aim to understand how melanoma cells become resistant to therapy over time, with the long-term view to identify new targets for therapies and improve human health. Melanoma arises from our pigment cells, called melanocytes. We and others have recently discovered that as melanoma cells become resistant to therapy, they inappropriately turn on genes from during embryonic development. We propose that adopting these embryonic characteristics, melanoma cells can rapidly adapt and escape therapy. To test this idea, we will engineer genetic models of zebrafish, because we can directly follow melanoma disease processes and perform intervention strategies in living animals. Importantly, zebrafish melanomas accurately model human melanoma and have been the basis of drug discovery and clinical trials. New findings in zebrafish will be tested in patient-derived samples to ensure human genetic disease relevance. Our work directly contributes towards our MRC Human Genetics Unit mission to address fundamental mechanisms of human genetic disease by using advanced animal models to interpret how genes are turned on and off to lead to melanoma drug resistance.