Vav1 and mutant k-Ras synergize in pancreatic ductal adenocarcinoma development: Lessons from mouse models
Professor of Cancer Studies, Israel
: J Clin Exp Oncol
Pancreatic Ductal AdenoCarcinoma (PDAC), the predominant form of pancreatic cancer, develops via Acinar-Ductal Metaplasia (ADM) and neoplastic precursor lesions, such as Pancreatic Intraepithelial Neoplasia (PanIN). Mutant K-Ras is present in >90% of PDAC and represents the most frequent and the earliest genetic alteration found in low-grade PanIN1A lesions. Identification of additional molecular lesions that affect PDAC is of cardinal importance. One such potential protein is Vav1, a hematopoietic specific signal transducer. Overexpression of Vav1 is implicated in human PDAC and is indicative of a worse survival rate. We generated transgenic mice that express Vav1, K-RasG12D, or both Vav1 and K-RasG12D (K-RasG12D, Vav1) in the pancreas. The number of lesions in the pancreata of K-RasG12D, Vav1 mice exceeded at least three times the number obtained in K-RasG12 mice already at three months post transgene induction. Also, the number of Ki-67 (indicative of proliferation) positive cells in K-RasG12D, Vav1 mice was significantly higher than in Vav1 or K-RasG12D transgenic mice. Thus, expression of Vav1 together with K-RasG12D in the pancreas has a dramatic synergistic effect enhancing ADM formation. Also, continuous Vav1 expression is needed for maintenance of the ADM lesions formed. Interestingly, a dramatic increase in phosphorylation of EGFR and activation of Rac1 was noted in pancreatic malignant lesions of K-RasG12D, Vav1 mice compared to the pancreas of the control transgenic mice. These results suggest that Vav1 regulates a cross-talk between tumor cells and the microenvironment resulting in up-regulation of signal transduction pathways. Identification of Vav1 as a protein that synergizes with mutant K-Ras in PDAC development might pave the way to choosing good candidates for therapeutic drug design.