Uncovering mechanisms of paediatric cancer progression and relapse using translational zebrafish modeling

Outcomes for cancer patients have improved over the past decades, yet survival rates remain low for pediatric patients with high-risk cancer subtypes including sarcomas, neuroblastoma and high-grade glioma. Furthermore, disease progression and/or relapse highly correlates with poor survival, independently of different treatment combinations, revealing an urgent need for novel targeted therapies. Improved therapeutic efficacy depends on advanced molecular understanding of tumor cells and the tumor microenvironment, as well as precision models for pre-clinical drug development, a deficiency of which currently exists for several hard-to-treat pediatric cancers compared to adult. Due to high-level genetic conservation and relative ease of manipulation, zebrafish have emerged as a popular model organism to study human cancer, with zebrafish providing many innovative opportunities to directly assess tumor cell growth, evolution, and heterogeneity in vivo. Furthermore, both targeted and combination therapies are facilitated by rapid testing using precision genetic models or xenograft transplantation approaches. Here, I will discuss my work developing and utilizing zebrafish models of pediatric cancers, with a focus on rhabdomyosarcoma (RMS), a devastating malignancy of the muscle. Using zebrafish models and mouse xenograft experiments, I defined important roles for multiple developmental signaling pathways in growth and self-renewal of RMS, including novel implications for the Wnt/PCP pathway (Hayes et al. 2018). More recently, I have extended similar modeling techniques to high-risk neuroblastoma and relapsed brain tumors and will discuss how fish models can be utilized to uncover biology related to relapse and metastasis. My future work aims to harness an intact tumor microenvironment and directly assess how interactions contribute to progression and relapse, in order to optimize therapeutic approaches for patients. Dr. Madeline Hayes is being interviewed for a Scientist position at the Research Institute