Cancer is a disease of the genome and epigenome, with most cancers developing numerous alterations throughout the course of disease. Many types of human cancers have now been extensively sequenced using next-generation technologies, and the scope of the alterations that are present in most malignancies has been truly eye-opening. Now, in this post-genomic era, we must sort through this wealth of data to identify the genes and pathways that that drive cancer progression, so that useful therapeutics can be developed. Our lab uses zebrafish models of pediatric cancers to help identify these new anti-cancer targets.
Approximately 70% of human genes have a zebrafish ortholog, and cancers made in transgeneic zebrafish develop in much the same way as human cancers. We use zebrafish primarily as a screening tool to identify oncogenic drivers of pediatric cancers using transgenic and transplantation approaches where genes of interest are over-expressed or knocked-out to assess their contribution to tumor progression. We also use zebrafish for in vivo drug screens so that we can better understand how tumors respond to therapy and develop resistance. A major benefit of zebrafish in this setting is the scale at which these experiments can be done. We can use hundreds to thousands of animals to develop statistically significant results, making us more confident in the relevance of our findings as we move to pre-clinical models and human samples.
Currently, our lab is following up on top hits from large-scale in vivo transplantation screen, in which we used the zebrafish pediatric T-cell acute lymphoblastic leukemia model to identify pathways that are associated with an increased ability of the T-ALL to form relapse (Blackburn et al. Cancer Cell, 2014). We have found that one hit from this screen, the phosphatase PRL3, may represent a useful drug target. As a whole, phosphatases are under-utilized therapeutic targets in cancer, and we are currently working to understand how phosphatases like PRL3 contribute to leukemia development and progression using both zebrafish models, human cell lines, and mouse xenografts (funded by NCI 4R00CA181500-03). Efforts are also underway to identify the unique gene expression profile of relapse-causing leukemia stem cells in acute lymphoblastic leukemia and to screen for compounds that can eliminate this important cell type (supported by COBRE).
If you have thoughts on these projects or are interested in a collaboration, please contact us!