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Project Title: Understanding the genetic and epigenetic regulation of cell behaviours in melanoma
Summary: Melanoma is an aggressive skin cancer with many advanced stage patients developing resistance to targeted treatment. With incidence and death rates rising, it has become crucial that more effective therapeutic options are made available. Skin cutaneous melanomas in particular have a high mutational burden making the effects of specific mutations difficult to instigate. Also, there is now a growing recognition of the role of epigenetic alterations in cancer development and progression. Studies using single-cell ATAC-seq on various cancer types have revealed that chromatin accessibility plays a significant role in influencing transcriptional profiles, however more detailed studies in melanomas remain limited.
Furthermore, there is a lack of understanding on how specific genetic mutations reshape the chromatin landscape of melanocytes during cancer progression and the epigenetic mechanisms enabling melanoma cell plasticity. Many studies have focused on identifying mutations, but few have mapped how these mutations alter chromatin accessibility and transcription factor binding. Understanding these mechanisms is crucial to reveal new therapeutic targets to improve treatment efficacy for advanced melanomas.
This project, therefore, aims to use stepwise-engineered human melanocyte models (PMID: 35482859) which replicates common melanoma mutations in a controlled system. By integrating their single-cell RNA- and ATAC-seq, effects of genetic mutations on chromatin and transcriptional changes can be linked, revealing altered regulatory networks and cellular heterogeneity. Finding will be experimentally validated and patient datasets will also be integrated to test the clinical relevance of our computational findings.
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