Deciphering the dynamics of melanoma plasticity

BACKGROUND Melanoma is a cancer of the melanocyte, with ~17500 new cases per year in the UK. Melanoma rapidly progresses and once metastatic is deadly. Immune Checkpoint Inhibitors are used as frontline treatment, yet ~40% of patients demonstrate resistance. A distinguishing feature of melanoma is its propensity for plastic adaptation, easily transitioning between different gene expression states. With the advent of ‘omics technologies we can profile melanoma cell states better than ever before. However, we lack understanding of the principles governing these fluctuations over space and time, particularly under the selective pressure of immune checkpoint blockade. This knowledge could potentially be harnessed to enhance patient outcomes through overcoming treatment resistance. My preliminary findings indicate consistent groups of genes correlatively co-expressed during melanocyte development and in melanoma, suggesting that embryonic mechanisms of gene regulation are still operating in melanoma. I contend that comparisons with embryonic melanocyte development could yield fresh insights into mechanisms of melanoma plasticity. AIMS I will apply tools to study melanoma lineage state transitions and uncover regulatory networks that mediate plastic potential. I will dissect these in a clinically relevant context for melanoma, that is colonisation of the lung. I aim to examine the impact inflammatory cytokines and surrounding extracellular matrices have on these regulatory networks, because of their relevance to immune surveillance of tumours and to encountering new microenvironments in metastasis. METHODS Using a panel of mouse melanoma cells that model the genetic and phenotypic diversity of human disease, I will create CRISPR-tagged fluorescent reporter cells that label different melanocytic lineage genes. Real-time imaging of these cells will reveal timings and spatial relationships of lineage gene expression states in melanoma, ultimately enabling identification and characterisation of melanoma cells with different plastic potentials. I will expand these insights into in vivo models of metastatic colonisation. Coupled with my gene expression mapping tools that define developmental lineage pathways and identify transition states, this work will provide insights into lineage-specific gene expression changes during metastatic progression. Altogether, these studies will reveal potential regulators of melanoma plasticity, which will be targeted in mouse and human tumour explant studies. HOW THE RESULTS OF THIS RESEARCH WILL BE USED This program will expand our insights into the mechanisms of plastic adaptation in melanoma—that could serve as paradigms for other cancers—revealing potential biomarkers for early detection of metastatic disease and providing new therapeutic targets to prevent metastatic relapse.