Discovering novel oncogenic pathways and new therapies using zebrafish models of sarcoma

Sarcoma is a type of cancer affecting connective, supportive, or soft tissue of mesenchymal origin. Despite rare incidence in adults (<1%), over 15% of pediatric cancers are sarcoma. Sadly, both adults and children with relapsed or metastatic disease have devastatingly high rates of mortality. Current treatment options for sarcoma include surgery, radiation, and/or chemotherapy; however, significant limitations exist with respect to the efficacy of these strategies. Strong impetus has been placed on the development of novel therapies and preclinical models for uncovering mechanisms involved in the development, progression, and therapy resistance of sarcoma. Over the past 15 years, the zebrafish has emerged as a powerful genetic model of human cancer. High genetic conservation when combined with a unique susceptibility to develop sarcoma has made the zebrafish an effective tool for studying these diseases. Transgenic and gene-activation strategies have been employed to develop zebrafish models of rhabdomyosarcoma, malignant peripheral nerve sheath tumors, Ewing's sarcoma, chordoma, hemangiosarcoma, and liposarcoma. These models all display remarkable molecular and histopathological conservation with their human cancer counterparts and have offered excellent platforms for understanding disease progression in vivo. Short tumor latency and the amenability of zebrafish for ex vivo manipulation, live imaging studies, and tumor cell transplantation have allowed for efficient study of sarcoma initiation, growth, self-renewal, and maintenance. When coupled with facile chemical genetic approaches, zebrafish models of sarcoma have provided a strong translational tool to uncover novel drug pathways and new therapeutic strategies.