PT  - JOURNAL ARTICLE
AU  - Salaymeh, Yaser
AU  - Farago, Marganit
AU  - Sebban, Shulamit
AU  - Shalom, Batel
AU  - Pikarsky, Eli
AU  - Katzav, Shulamit
TI  - Vav1 and mutant K-Ras synergize in the early development of pancreatic ductal adenocarcinoma in mice
AID  - 10.26508/lsa.202000661
DP  - 2020 May 01
TA  - Life Science Alliance
PG  - e202000661
VI  - 3
IP  - 5
4099  - http://www.life-science-alliance.org/content/3/5/e202000661.short
4100  - http://www.life-science-alliance.org/content/3/5/e202000661.full
SO  - Life Sci. Alliance2020 May 01; 3
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.