Synergistic Effects of Vav1, a RacGTPase Exchange Factor, and the G-Protein Mutant K-Ras, in Pancreatic Cancer Development

The 5-year survival rate of pancreatic ductal adenocarcinoma (PDAC) is less than 5% and has remained stubbornly unchanged. PDAC develops via acinar-to-ductal metaplasia (ADM) that can convert to pancreatic intraepithelial neoplasia (PanIN) and progress to PDAC. Mutant K-Ras is present in >90% of patients with PDAC and is thought to lock cells that have undergone ADM in the ductal state, preventing restoration of normal differentiation and creating a reservoir of cells susceptible to additional oncogenic changes. Signal transduction processes and inflammation enhance ADM. One protein that might cooperate with mutant K-Ras in PDAC development is Vav1, a pivotal signal transducer in the hematopoietic system. Vav1 is best known for its tyrosine phosphorylation dependent function as a GDP/GTP exchange factor (GEF) for Rho/RacGTPases, an activity that regulates cytoskeletal rearrangement. We and others have detected ectopic expression of Vav1 in PDAC, indicative of a worse survival rate.

To find out whether Vav1 plays a role in PDAC development and if co-operates with oncogenic K-Ras, we have generated novel mouse strains expressing Vav1, K-Ras^G12D or both Vav1 and K-Ras^G12D in the pancreas. Co-expression of Vav1 and K-Ras^G12D dramatically increases ADM, and does so substantially faster than K-Ras^G12D alone, strongly suggesting that the two oncogenes synergize to enhance pancreatic tumor development. The increase in pancreatic lesions was also accompanied with an intensification in various signaling pathways, such as ERK and EGFR phosphorylation, and Rac1 activation. Treatment of these mice with either erlotinib (an EGFR inhibitor) or azathioprine (blocks Vav1 activity as a GEF) reduces markedly the appearance of pancreatic malignant lesions. Notably, removal of doxycycline, thus ablating the expression of Vav1 in the pancreas of Vav1 and K-Ras^G12D bi-transgenic mice led to a significant reduction in malignant lesions, further highlighting the necessity of expression of both oncogenes to cancer development in the pancreas.

Our studies indicate that the proteins Vav1 that acts as a GEF and oncogenic K-Ras that acts a G-protein contribute together to enhancement of signaling pathways that result in enhancement of pancreatic cancer. 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.