Zebrafish Modeling of PAX3-FOXO1 Driven Rhabdomyosarcoma
Background
Sarcomas are cancers that derive from soft tissue including skeletal muscle, fat, and connective tissue. The Amatruda lab uses zebrafish that express human cancer genes as a model to study sarcoma origins and their underlying biology. Zebrafish share over 70% of their genes with humans, and approximately 84% of known human disease genes have a zebrafish counterpart.
Project Goal
Here, I propose to develop a zebrafish model of alveolar rhabdomyosarcoma (ARMS), a primarily solid tumor with characteristics that resemble embryonic skeletal muscle. These tumors have a poor prognosis, and are genetically characterized by the presence of the fusion of two known genes, PAX3 or PAX7 to FOXO1, to create a novel and active PAX3/7-FOXO1 protein. This new protein transforms normal cells into cancerous cells, yet the exact mechanisms underlying this transformation are not well understood. There is debate as to what cell types are most susceptible to these mutations, and a better understanding would help inform therapies.
I will generate zebrafish that have a human PAX3-FOXO1 gene fusion integrated into their DNA. I will study how ARMS tumors are generated, what the PAX3-FOXO1 molecular targets are, and the signaling pathways these cancers leverage to progress and metastasize. In addition, I will use this ARMS zebrafish model to perform a high-throughput drug screen to identify FDA approved drugs that inhibit PAX3-FOXO1 function in vivo. These models will facilitate the identification of rationally designed therapies, with the ultimate goal of moving small molecules into the clinic to improve ARMS patient outcomes.
