Vav1 and Mutant K-Ras Synergize in Pancreatic Ductal Adenocarcinoma Development: Lessons from Mouse Models

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.

Materials 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 analyzed at different times post transgenes induction.

Results and discussion:

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.