In normal tissue, (in this case normal melanocytes) cells “behave”. They grow in the correct numbers and to the correct size.
Once a group of cells has acquired a genetic mutation, typically in an oncogene or tumor suppressor, these cells begin to behave abnormally by dividing excessively or changing their architecture and behavior. Yet, these cells are still not truly cancer, only pre-cancer.
We have discovered that, in the case of melanoma, rare cells in this field of pre-cancerous cells change their cell identity to appear more like an embryonic neural crest cell. This is where melanoma cancer starts, or initiates, and this is where we are targeting our studies.
By combining a powerful and flexible zebrafish melanoma model with molecular discoveries from human melanoma, we aim to accomplish the following:
- Profile the earliest transcriptional and epigenetic events that occur during melanoma initiation. We are able to uniquely accomplish this with the zebrafish model because we can see these first cancer cells earlier than previously possible.
- Modify the epigenetic landscape in the pre-cancerous melanocytes and determine the outcome on melanoma formation. With the genetic tools available in the zebrafish including gain- and loss-of-function approaches, we can modify both specific loci and broad aspects of the chromatin landscape in developing zebrafish to determine the effect on melanoma formation.
- Identify chemicals (i.e. ideally therapeutic drugs) that prevent melanoma formation. The zebrafish is ideally suited to rapid and large-scale screens to identify such potential therapies.
- Develop diagnostic tools to detect the earliest changes in pre-cancerous melanocytes that signify conversion to cancer. Earlier detection may allow for earlier treatment and improved outcomes for patients.
- Understand how metabolic rewiring in response to changes in nutrient availability alters tumor onset
- Identify novel changes in the genomes of human melanomas (mutations) that change gene expression and lead to cancer formation