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.

Over 16,000 people in the UK will be diagnosed with melanoma this year. Incidence is rising, and melanoma is now one of the most common cancers in young adults, especially young women. Despite improvements in targeted and immune-based therapies, many patients will succumb to melanoma due to drug resistance caused by disease intratumour heterogeneity generated by genetic mutations, plasticity of transcriptional cell states and a complex tumour microenvironment.
Our research vision is to harness advanced zebrafish models to investigate the mechanisms that underpin the dynamic cellular transcriptional heterogeneity in melanoma, with a view to inform therapy and improve human health. We hypothesise that dysregulated developmental lineages are a significant cause of tumour cell transcriptional heterogeneity (cell states) and the adaptive responses to therapy. These dysregulated developmental states in cancer provide a rich source of new drug targets. However, modelling melanoma-driving disease processes and intervention strategies in vivo remains a significant challenge in translating targets to the clinic.
Zebrafish are ideal for this purpose because: (1) we can interrogate melanocyte development and cancer in the same system in 4D across life span; (2) they are highly accessible for imaging at single-cell resolution; and (3) genome editing technologies and drug treatments enable perturbation experiments to directly test melanoma dependencies (genotype to phenotype). Importantly, zebrafish melanomas accurately depict the genetics and pathology of human melanoma and have been the basis of drug discovery and clinical trials. Our models are designed to capture both superficial and nodular cutaneous melanoma growth, with or without BRAF V600E mutations. We will delineate mechanisms that regulate the dynamics of disease-associated cell states and relate these to outcomes (cell state to phenotype). We will apply our findings to patient-derived samples and leverage human genomic datasets to ensure human genetic disease relevance.
Working collaboratively, we deliver on the HGU mission to discover fundamental mechanisms of human genetic disease within the context of melanocyte development and disease through two main Aims:
Aim 1: Discover genetic McSC lineage mechanisms in development and disease
Aim 2: Target melanocyte and melanoma cells states in 4D zebrafish models
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 the genetic and transcriptional states that lead to melanocyte dysfunction.