Vav1 and mutant K-Ras synergize in the early development of pancreatic ductal adenocarcinoma in mice

To explore the contribution of Vav1, a hematopoietic signal transducer, to pancreatic ductal adenocarcinoma (PDAC) development, we generated transgenic mouse lines expressing, Vav1, K-Ras(G12D), or both K-Ras(G12D) and Vav1 in pancreatic acinar cells. Co-expression of Vav1 and K-Ras(G12D) synergistically enhanced acinar-to-ductal metaplasia (ADM) formation, far exceeding the number of lesions developed in K-Ras(G12D) mice. Mice expressing only Vav1 did not develop ADM. Moreover, the incidence of PDAC in K-Ras(G12D)/Vav1 was significantly higher than in K-Ras(G12D) mice. Discontinuing Vav1 expression in K-Ras(G12D)/Vav1 mice elicited a marked regression of malignant lesions in the pancreas, demonstrating Vav1 is required for generation and maintenance of ADM. Rac1–GTP levels in the K-Ras(G12D)/Vav1 mice pancreas clearly demonstrated an increase in Rac1 activity. Treatment of K-Ras(G12D) and K-Ras(G12D)/Vav1 mice with azathioprine, an immune-suppressor drug which inhibits Vav1’s activity as a GDP/GTP exchange factor, dramatically reduced the number of malignant lesions. These results suggest that Vav1 plays a role in the development of PDAC when co-expressed with K-Ras(G12D) via its activity as a GEF for Rac1GTPase.