ia2 mutant: a zebrafish model of spontaneous pancreatic carcinomas and soft-tissue sarcomas

Pancreatic adenocarcinoma is one of the most lethal of human malignancies, and, despite the advances in the understanding of the molecular events responsible for its progression, ultimate therapeutic options are lacking. Soft-tissue sarcomas (STSs) are mesenchymal tumors that arise from muscle, fat and connective tissue. The mechanisms underlying STS development are still largely unclear, because of the rarity and heterogeneity of patient samples. Animal models, particularly those of primary tumors, are therefore indispensable tools to understand STS and pancreatic cancer biology and enable preclinical studies of novel drugs and therapies. We identified a mutant, named ia2 and genetically defined by a 15 Mb-long deletion of chromosome 1, as a new zebrafish model of primary pancreatic carcinomas and STSs. The mutation was generated by the insertion of a GFP-expressing transgene, designed for other aims. Homozygous ia2 mutants display an embryonic lethal phenotype, characterized by relevant developmental delay and morphological alterations, with evidence of cellular disaggregation. The heterozygous mutant has a slight reduction in survival rate, but no morphological defects are visible when compared with the wild-type. Nevertheless, it develops spontaneous tumor masses with an incidence rate of 32% by 16 months. Histological analysis revealed aggressive, malignant tumors, with a strong spindle cells stromal component typical of STSs or of the sclerotic reaction occurring in pancreatic carcinomas. Thus, the two main tumor histotypes produced by ia2 mutants are STS and pancreatic cancer. The GFP expression permits a rapid and early identification of ia2 heterozygotes, making ia2 mutant a manageable model to study STS and pancreatic carcinoma biology.