Our ZF-MEL-CHEMBIO programme has three main objectives. First, we are screening for new drugs and drug-leads in the zebrafish embryo. Toward this objective, we have developed a new automated handling system with state-of-the-art imaging to capture the melanocyte developmental lineage developing in live animals. In particular, we have focused on a set of cells called the melanocyte stem cells. In melanoma, a sub-population of cells have stem-cell like features and are resistant to treatment. Drugs that control the melanocyte stem cell in development may be relevant to the melanoma stem cell population in cancer. In Aim 2, we are understanding the targets of our drugs in a living system. Most drugs have many targets in living systems, and we know little about these targets and how the drugs actually work in the disease context. We have discovered that an antibiotic that is commonly used to treat parasitic and bacterial infections has a new target in zebrafish and in cancer. We are currently validating these ideas in our zebrafish model system. In Aim 3, we use the zebrafish system to test of new targets are important in melanoma progression and if we can treat these cancers with our drugs. This work is on-going, but we are excited by the possibility that one of our new target genes may be accelerating melanoma progression - this may validate the importance of targeting this gene product in melanoma.
Our work has identified new transcriptional and metabolic regulators of melanocyte stem cells, including Tfap2b, ALDH2 and PRL3. Importantly, these findings are not simply about zebrafish melanocyte stem cells but reflect new underlying mechanisms in human skin melanocyte stem cells. Further, we find these cell states to be important in residual disease following melanoma targeted therapy. Therefore, they provide new therapeutic opportunities. This work has been published in peer reviewed journals (e.g. Cell Reports, Developmental Cell, Cell Chemical Biology, Development, Disease Models & Mechansims) and presented widely at conferences within Europe and around the world (e.g. Society for Melanoma Research, Melanoma Research Alliance, Zebrafish Disease Models Community).
