Wilms' tumor, also known as nephroblastoma, is the most common pediatric renal tumor. While treatment outcome has improved over the recent decade, there is a strong clinical need to improve therapies in order to both minimize secondary effects occurring later in life due to current treatments, and to find more effective therapies for high-risk histological subtypes and relapsed patients. A multitude of driver gene mutations has been documented for Wilms' tumor, affecting either aspects of differentiation, proliferation, genome maintenance, or biogenesis and maturation of microRNAs (miRNAs). Especially the latter is a unique intriguing feature of this tumor. Unfortunately genetic mouse models for these pediatric tumors are limited. In this project we want to exploit a recently generated and penetrant model for Wilms' tumor obtained in Xenopus tropicalis using CRISPR-mediated targeting of the p53 and RB pathways. Additional models targeting tumor suppressor microRNAs and genes involved in miRNA processing will be generated. Via extensive transcriptomic and epigenomic profiling and interspecies comparison with the existing mouse model and human clinical samples, we want to get a more clear picture of the molecular signatures underlying the etiology of different Wilms' tumor subtypes. As such we foresee to identify possible vulnerabilities that can be explored via CRISPR-mediated dependency mapping in the Xenopus models, with the aim of finding novel targets for therapy.