My laboratory studies mechanisms underlying cell survival and migration during embryogenesis and disease. We are particularly interested in embryonic signaling pathways that are reactivated in tumors to promote cancer metastasis. An excellent model of cell migration during development is the neural crest, a multipotent cell population that migrates extensively in the vertebrate embryo to generate a variety of cell types, including pigment cells, neurons, glia and elements of the craniofacial skeleton. Neural crest progenitors are initially generated in the neuroepithelium of the neural tube, so they must first undergo an epithelial-mesenchymal transition (EMT) to form premigratory neural crest cells. These cells then divide and navigate through a number of embryonic tissues that secrete potential pro-apoptotic signals, before arriving at their final destination to differentiate. Thus, neural crest cells have evolved mechanisms to coordinate a number of cellular processes that involve regulation of cell survival, proliferation and migration, as well as modifications of cell-to-cell adhesion that involve dynamic interactions with the extracellular matrix. Disrupting these processes during human development causes a number of congenital diseases (neurocristopathies) and cancers such as melanoma and neuroblastoma. Importantly, recent studies have shown that reactivation of neural crest transcription factors in primary tumors promotes tumor invasiveness and metastasis.
To study neural crest migration and metastasis, we use the zebrafish model because the optically clear embryos and adult pigment mutants allow fluorescently labeled cells and tumors to be monitored using real-time imaging techniques. In addition, the molecular pathways underlying mammalian embryonic development are highly conserved in zebrafish, and a number of zebrafish models of human diseases are now established, including neural crest-derived cancers. Also, cell transplantation experiments can be performed in embryos and adult fish, allowing cell autonomous and non-autonomous mechanisms of cell migration and metastasis to be investigated. Thus, the attributes of the zebrafish system provide a unique opportunity to determine how developmental mechanisms that control cell migration during development are subverted in pediatric diseases and cancer metastasis. Current projects include the following:
- Identify genes functioning downstream of Foxd3 that regulate neural crest migration and survival. Foxd3 is a transcription factor essential for stem cell survival and neural crest migration, but the targets of Foxd3 are unknown. This project aims to identify the Foxd3 targets using both genetic and biochemical analyses in zebrafish and human cell culture.
- Analyze new neural crest mutants in zebrafish. We have isolated a number of recessive ENU-induced mutants with different neural crest migration, differentiation, or survival phenotypes. The aim of this project is to clone the genes affected in these mutants and determine the molecular mechanism(s) underlying the migration phenotypes.
- Generate metastasis models in zebrafish. Metastasis results from a multistep process requiring acquisition and selection of multiple genetic and epigenetic lesions within the unstable cancer genome. The aim of this project is to generate zebrafish metastasis models of neural crest-derived tumors such as melanoma, neuroblastoma, and schwannoma, using genetic approaches with established mutant and transgenic lines.