Zebrafish model of KRAS-initiated pancreatic cancer

Pancreatic cancer constitutes a genetic disease in which somatic mutations in the KRAS proto-oncogene are detected in a majority of tumors. KRAS mutations represent an early event during pancreatic tumorigenesis that crucial for cancer initiation and progression. Here, we established a zebrafish pancreatic cancer model that highly recapitulates human pancreatic intraepithelial neoplasia (PanIN) development. We established a novel system combining CRE/Lox technology with the GAL4/UAS system to express oncogenic KRAS in the ptf1a domain temporarily. In this system, zebrafish developed PanIN at an 11.1% rate by 24 and 36 weeks after KRAS(G12V) induction. The histological and immunohistochemical profiles of these experimental tumors bore striking resemblance to human PanIN. Within the whole abnormal area, the entire spectrum of differentiation ranging from PanIN-1 to PanIN-3 was noted. Immunohistochemical analysis including Alcian blue, CK-18, cadhedrin-1, and DCLK1 staining confirmed the PanIN region as a characteristic pancreatic cancer precursor lesion. Taken together, these findings demonstrate that this zebrafish model may offer the possibility of an experimental and preclinical system to evaluate different strategies for targeting pancreatic tumors and finally improve the outcome for the patients with pancreatic tumors.