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.
Highlights
Vav1, a signal transducer protein which is physiologically expressed in the hematopoietic system, was first identified as an in vitro–activated oncogene (Katzav et al, 1989)
Several recent studies have indicated that mutations in various domains of the Vav1 protein are present in human cancers such as adult T-cell leukemia/lymphoma (Kataoka et al, 2015), lung adenocarcinoma and squamous cell carcinomas (Campbell et al, 2016), and peripheral T-cell lymphomas (Abate, da Silva-Almeida et al, 2017)
We show that expression of Vav1 together with that of K-RasG12D in the pancreas has a synergistic effect in enhancing acinarto-ductal metaplasia (ADM), which leads eventually to an increase in the number of pancreatic intraepithelial neoplasia (PanIN)
Summary
A signal transducer protein which is physiologically expressed in the hematopoietic system, was first identified as an in vitro–activated oncogene (Katzav et al, 1989). It functions as a GDP/GTP exchange factor (GEF) for Rho/RacGTPases, an activity that is stringently controlled by tyrosine phosphorylation (Crespo et al, 1997). The accumulating data, clearly point to an important role of ectopically expressed wtVav in pancreatic cancer (Fernandez-Zapico et al, 2005; Huang et al, 2016), possibly through its activity as a GEF that regulates cytoskeletal organization and/or through its activity as a signal transducer that can affect growth factor/cytokine production. The mechanisms that mediate this protumorigenic role of Vav in pancreatic cancer and the stages during tumorigenesis, at which such mediation occurs, are unknown
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