To explore the contribution of Vav1, a hematopoietic signal transducer, to pancreatic ductal adenocarcinoma (PDAC) development, we generated transgenic mouse lines expressing, Vav1, K-RasG12D, or both K-RasG12D and Vav1 in pancreatic acinar cells. Co-expression of Vav1 and K-RasG12D synergistically enhanced acinar-to-ductal metaplasia (ADM) formation, far exceeding the number of lesions developed in K-RasG12D mice. Mice expressing only Vav1 did not develop ADM. Moreover, the incidence of PDAC in K-RasG12D/ Vav1 was significantly higher than in K-RasG12D mice. Discontinuing Vav1 expression in K-RasG12D/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-RasG12D/Vav1 mice pancreas clearly demonstrated an increase in Rac1 activity. Treatment of K-RasG12D and K-RasG12D/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-RasG12D via its activity as a GEF for Rac1GTPase.
Bibliographical noteFunding Information:
We are indebted to Shirley Smith for editing the manuscript and to Dr Dror Gal, Prof. Ittai Ben-Porath, and Prof. Yuval Dor for advice on mouse manipulation. This work was supported, in part, by grants from the Israel Academy of Sciences, the Israel Cancer Association (ICA) with the generous assistance of the USA Friends of ICA in Honor of Laurence Holzman and Felicia Needleman; The Israel Cancer Research Fund; The Hubert H Humphrey Center for Experimental Medicine and Cancer Research; The Alex U Soyka Pancreatic Cancer Research Project; and a donation from Vibeke Lichten.
© 2020 Salaymeh et al.