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


ABSTRACT: 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.

SUBMITTER: Salaymeh Y 

PROVIDER: S-EPMC7156281 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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

Salaymeh Yaser Y   Farago Marganit M   Sebban Shulamit S   Shalom Batel B   Pikarsky Eli E   Katzav Shulamit S  

Life science alliance 20200410 5


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<sup>G12D</sup>, or both K-Ras<sup>G12D</sup> and Vav1 in pancreatic acinar cells. Co-expression of Vav1 and K-Ras<sup>G12D</sup> synergistically enhanced acinar-to-ductal metaplasia (ADM) formation, far exceeding the number of lesions developed in K-Ras<sup>G12D</sup> mice. Mice expressing only Vav1 did not dev  ...[more]

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