TY - JOUR
T1 - Vav1 and mutant K-Ras synergize in the early development of pancreatic ductal adenocarcinoma in mice
AU - Salaymeh, Yaser
AU - Farago, Marganit
AU - Sebban, Shulamit
AU - Shalom, Batel
AU - Pikarsky, Eli
AU - Katzav, Shulamit
N1 - Publisher Copyright:
© 2020 Salaymeh et al.
PY - 2020/5
Y1 - 2020/5
N2 - 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.
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.
UR - http://www.scopus.com/inward/record.url?scp=85083195473&partnerID=8YFLogxK
U2 - 10.26508/lsa.202000661
DO - 10.26508/lsa.202000661
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C2 - 32277014
AN - SCOPUS:85083195473
SN - 2575-1077
VL - 3
JO - Life Science Alliance
JF - Life Science Alliance
IS - 5
M1 - e202000661
ER -