Generating Fusion-Positive Alveolar Rhabdomyosarcoma in Danio Rerio
Rhabdomyosarcoma is the most common pediatric soft tissue cancer, afflicting approximately 4.6 children out of every million in the United States (Gurney et al., 1996). The malignancy is divided into two subtypes, alveolar (ARMS) and embryonal (ERMS). ARMS is particularly aggressive and pathognomonic with oncogenic chromosomal translocations between the PAX genes and the fork-head transcription factor (FOXO1), ultimately creating de novo transcription factors that disrupt developmental pathways and predispose to cancer. PAX3-FOXO1+ ARMS is often more aggressive and has a worse prognosis, with survival rates of only 30% for patients with relapsed and/or metastatic disease. Yet to date, mechanistic differences between PAX3-FOXO1+ and PAX7-FOXO1+ ARMS have not been defined.
The Langenau Lab specializes in and is at the forefront of developing novel disease models in Danio rerio (zebrafish). Combined with the lack of robust alveolar rhabdomyosarcoma models, my project will generate faithful and comprehensive models of both subtypes of fusion+ ARMS using genome editing and cre/lox technology that I have developed. When successful, these models will be useful for identifying key differences in PAX3-FOXO1+ and PAX7-FOXO1+ ARMS, including likely differences in cell-of-origin, TPCs and metastatic capacity, providing an explanation of why PAX3-FOXO1+ does worse clinically. My work also represents the first time precision animal modeling of endogenous translocation will be modeled in vivo, an approach, that when successful, will be applied to a wide array of pediatric cancers that are initiated by translocation events.