Understanding spatial and temporal clonal evolution of melanoma and its niche under treatment pressure

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Melanoma has a poor prognosis for metastatic disease. Despite improvements in its treatment, approximately 50% of patients still develop resistance with widespread relapse and very high mortality. There is growing evidence that a high degree of intra-tumour heterogeneity correlates with poor disease prognosis in patients. Despite large efforts to disentangle the clonal dynamics via genomic and phenotypic studies, our understanding remains rudimentary. This project, therefore, takes a more controlled approach studying how different melanoma clones compete and differ in their vulnerabilities before and during targeted therapy. The ultimate aim is to gain mechanistic insight about how to decrease the fitness of resistant melanoma clones, enabling a more durable therapeutic response. I will generate intra-tumour heterogeneity with a novel approach that stochastically introduces defined clinically relevant oncogenic mutations coupled with unique fluorophores within a tumour that can be tracked in vivo using intravital imaging. The unique fluorophores will enable ex vivo isolation of different clones and downstream mechanistic analysis of changes in signalling and gene expression. Moreover, I will investigate how the tumour microenvironment changes when clones with specific mutations expand. Knowledge acquired by these studies will be exploited to test better treatment strategies in vivo.