PO-196 Vav1 and Mutant K-Ras synergize in pancreatic ductal adenocarcinoma development: lessons from mouse models

Abstract

Introduction The overall 5 year survival rate of Pancreatic Ductal Adenocarcinoma (PDAC) is less than 5% and has remained stubbornly unchanged long time ago, despite the efforts in preclinical and clinical science. PDAC, the main 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 is the most frequent and the earliest genetic alteration, being found in low-grade lesions. Identification of other molecular lesions that affect PDAC is of cardinal importance. One such potential protein is Vav1, a hematopietic specific signal transducer. Overexpression of wild-type Vav1 is implicated in human cancers, such as neuroblastoma, lung and PDAC. The expression of Vav1 in PDAC is indicative of a worse survival rate. Our goal was to determine whether Vav1 plays a causative or facilitatory role in-vivo in PDAC development. Material and methods We generated several transgenic mouse models that express Vav1, K-Ras G12D , or Vav1 and K-Ras G12D in the pancreas. K-Ras was induced by tamoxifen and Vav1 by Dox. Pancreata were analysed at different times post transgenes induction. Results and discussions Vav1 Expression together with K-Ras G12D in the pancreas has a dramatic synergistic effect enhancing ADM formation already at 3 months post transgene induction, resulting in at least 3 times the number of lesions in the pancreata of Vav1;K-Ras G12D mice compared to K-Ras G12 mice. No lesions were observed in the pancreas of Vav1 mice. The number of Ki-67 positive cells in Vav1;K-Ras G12D mice was significantly higher than in Vav1 or K-Ras G12D transgenic mice. The increase of pancreatic lesions was also accompanied with an increase in staining of Sox9 and Keratin and various pathways such as pERK, pEGFR and Rac1-GTP., highlighting the synergistic effect of Vav1 and K-Ras G12D in the development of PDAC. Notably, removal of Dox, thus ablating the expression of Vav1 in the pancreas of Vav1;K-Ras G12D led to a significant reduction in malignant lesions, thus further highlighting the necessity of expression of both oncogenes to cancer development in the pancreas. Conclusion Vav1 contributes to the development of malignant lesions in the pancreas when expressed with mutant K-Ras. 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.