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Chemical Biology in Zebrafish: Drug-Leads and New Targets in the Melanocyte Lineage and Melanoma

Periodic Reporting for period 4 - ZF-MEL-CHEMBIO (Chemical Biology in Zebrafish: Drug-Leads and New Targets in the Melanocyte Lineage and Melanoma)

Reporting period: 2020-03-01 to 2022-02-28

Melanoma kills over 20,000 Europeans each year, and incidence continues to rise. Despite important progress in therapy for patients, most patients with metastatic melanoma ultimately succumb to the disease. Our objective is to identify new drugs and drug-leads that can act alone or be used in combination with current available therapies to enhance drug effectiveness and/or overcome drug resistance. Our work, and the work of others, has shown that a melanocyte developmental lineage programme becomes activated during melanoma, and that this cancer requires these developmental genes for survival. We are using the zebrafish system to study melanocyte development and to understand how these pathways become misregulated in cancer. This is relevant because zebrafish develop melanomas that look, develop and progress in a very similar way human melanomas. We are screening for new drugs and drug-leads in our zebrafish system, with a view to applying these to the human cancer condition.

Our work has achieved new insight into melanocyte stem cell biology. Specifically, we have identified transcriptional and metabolic pathways that are directly relevant to human melanoma. Through our small molecule screens (Aim1), we have used imaging, gene editing and chemical biology to show new regulators of stem cell pathways (Aim 2), and have directly shown that these are relevant to zebrafish and human cancer (Aim 3). Overall, these are among the first insights into the molecular mechanisms of melanocyte stem cells in zebrafish.
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).
We have developed an automated screening platform that is allowing us to visualize the melanocyte stem cells for the very first time in unpresidented detail. Not only are we seeing new biology, but the system allows us to automate small molecule screening. This is the first time this has been achieved, and is an exciting advance on the current state-of-the-art. Please see Figure 1 for an example of the melanocyte stem cell lineage that has been stimulated to have enhanced numbers of cells, and Figure 2, that shows the set up of our screening platform.

As part of our work we preformed new lineage tracing technologies in zebrafish adult cancers (Travnickova et al., 2022) and developed new mechanisms to administer zebrafish drugs via pellets (Lu & Patton 2022). These are new technologies in our zebrafish community and we have already been asked for protocols and tools by many other labs.
Our new automated screening system for identifying new drugs in zebrafish (Aim 1)