RT Journal Article
SR Electronic
T1 Vav1 and mutant K-Ras synergize in the early development of pancreatic ductal adenocarcinoma in mice
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e202000661
DO 10.26508/lsa.202000661
VO 3
IS 5
A1 Yaser Salaymeh
A1 Marganit Farago
A1 Shulamit Sebban
A1 Batel Shalom
A1 Eli Pikarsky
A1 Shulamit Katzav
YR 2020
UL https://www.life-science-alliance.org/content/3/5/e202000661.abstract
AB 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.