Pediatric Cancer Models in Zebrafish

Abstract

Pediatric cancer is a leading cause of death idraw n children and adolescents. Improvements in pediatric cancer treatment that include the alleviation of longterm adverse effects require a deeper understanding of the genetic, epigenetic, and developmental factors driving these cancers. Here, we review how the unique attributes of the zebrafish model system in embryology, imaging, and scalability have been used to identify new mechanisms of tumor initiation, progression, and relapse and for drug discovery. We focus on zebrafish models of leukemias, neural tumors and sarcomasthe most common and difficult childhood cancers to treat. Childhood and Adolescent CancerPediatric cancer is one of the leading causes of death in children and adolescents (age 0-19 years) and is mainly comprised of leukemias, cancers of the nervous system, and sarcomas [1]. Recent genomic profiling efforts to better understand the etiology of this group of diseases have enabled the stratification of tumor types based on molecular signatures and have led to the identification of potential genetic drivers and cooperating molecular events that underlie the development of different pediatric cancers. Most pediatric malignancies are mutationally quiet and are thought to be driven by a single driver gene, a fusion oncoprotein, or structural/copy number alterations [2,3]. In contrast, adult tumors frequently exhibit high mutational burdens, likely due to a longer period of mutational acquisition under selective pressure [2,3]. Despite these differences, however, pediatric cancer treatments are still largely modeled after treatments designed for the adult version of the disease and can cause debilitating, long-term side effects when administered to children. The development of robust preclinical pediatric cancer models that accurately recapitulate these diseases will ultimately be necessary for the design of more precise, targeted therapies to improve outcomes for pediatric cancer patients. Here, we discuss how the use of zebrafish has advanced the pediatric cancer field as a preclinical model for gene and drug discovery. HighlightsZebrafish develop tumors that are histologically and genetically similar to human tumors. Zebrafish enable the rapid identification of molecular drivers of tumor development and can be used to model cancers with unknown cells of origin using heatshock and β-actin promoters.Zebrafish models are amenable to highthroughput drug screening through larval drug submersion approaches, as well as transplantation of primary patient tumors into immunocompromised lines.Tumor-cell dynamics can be visualized in vivo throughout the lifetime of the animal by coupling oncogenes to fluorescent markers.

Tipping the Scales With Zebrafish to Understand Adaptive Tumor Immunity

“…Through exhaustive comparison of the human and zebrafish genome assemblies, it was found that 82% of disease-causing human genes have at least one zebrafish ortholog ( Howe et al, 2013 ). This level of conservation has led to the development of a wide array of cancer models in zebrafish ( Casey and Stewart, 2018 ; Hason and Bartůněk, 2019 ; Casey and Stewart, 2020 ; Elliot, 2020 ). Through the years of ongoing research, the pathological similarities of cancer and preservation of the immune components have also been well established between zebrafish and humans.…”

Preclinical In Vivo Modeling of Pediatric Sarcoma—Promises and Limitations

“…While zebra fish models might not be as translatable as mouse models due to their non-mammal nature, shorter generation times, higher scalability, lower costs, extracorporeal embryonic development, and skin transparency (allowing live cell imaging) render them a powerful and complementary modeling tool for pediatric tumors [ 150 ]. Good examples of such a genetically-engineered zebrafish models for pediatric sarcoma can be found in the study of Parant et al on MPNST [ 151 ] as well as the recent review of Casey et al on sarcoma zebrafish models for pediatric cancers [ 152 ]. For rhabdomyosarcoma an eRMS model expressing KRAS G12D in muscle satellites cells via Rag2 promoter by Langenau et al [ 153 , 154 ] as well as an aRMS model, systemically expressing the PAX3-FOXO1 fusion by Kendall et al [ 155 ] were developed to date.…”

Unveiling Tumor Microenvironment Interactions Using Zebrafish Models

“…Noticeably, an impetus to move zebrafish models toward personalized and precision medicine has been generated and is currently moving with considerable speed (Fior et al, 2017 ; Casey and Stewart, 2020 ; Costa et al, 2020a ; Fazio et al, 2020 ). In regard to zPDX, both larval and adult models have demonstrated their remarkable potential to help guide clinical decisions; deciding which developmental stage to use, however, will likely depend on (1) the patient's timeframe, (2) the quantity of patient-derived material, (3) the number of therapeutic options planned to be tested, and (4) the tumor/TME aspects of interest.…”