Targeting Pancreatic Cancer Metastasis by Inhibition of Vav1, a Driver of Tumor Cell Invasion

Abstract

Pancreatic cancer, one of the most lethal forms of human cancer, is largely resistant to many conventional chemotherapeutic agents. While many therapeutic approaches focus on tumor growth, metastasis is a primary factor contributing to lethality. Therefore, novel therapies to target metastatic invasion could prevent tumor spread and recurrence resulting from local and distant metastasis. The protein Vav1 is aberrantly expressed in over half of pancreatic cancers. Its expression promotes activation of Rac and Cdc42 and leads to enhanced invasion and migration, as well as increased tumor cell survival and proliferation, suggesting that Vav1 could be a potent therapeutic target for pancreatic cancer. The purine analogue azathioprine, well-known for its function as an anti-inflammatory compound, was recently shown to function by inhibiting Vav1 signaling in immune cells. We therefore hypothesized that azathioprine could also inhibit Vav1 in pancreatic tumor cells to reduce its pro-invasive functions. Indeed, we have found that treatment of cultured pancreatic tumor cells with azathioprine inhibited Vav1-dependent invasive cell migration and matrix degradation, through inhibition of Rac and Cdc42 signaling. Further, azathioprine treatment decreased metastasis in both xenograft and genetic mouse models of pancreatic cancer. Strikingly, metastasis was dramatically reduced in Vav1-expressing tumors arising from p48Cre/+, KRasG12D/+, p53F/+ mice. These inhibitory effects were mediated through Vav1, as Vav1-negative cell lines and tumors were largely resistant to azathioprine treatment. These findings demonstrate that azathioprine and related compounds could be potent anti-metastatic agents for Vav1-positive pancreatic tumors.

Coexpression of UCA1 and ITGA2in pancreatic cancer cells target the expression of miR‐107 through focal adhesion pathway

“…were validated by analyzing the expression of several rPaC-related proteins, including ITGA3, Src, FAK, and Rac. These proteins had been reported activated in the progression and metastasis of PaC (Kanteti, Batra, Lennon, & Salgia, 2016;Razidlo et al, 2015;Xu, Wang, An, & Xu, 2013), which also supported our results. And we further verified PaC cells transfected with ITGA2 and miR-107 inhibitors could stimulate the expression of those proteins.…”

Vav1 and mutant K-Ras synergize in the early development of pancreatic ductal adenocarcinoma in mice

“…Its binding to Rac1 blocks Vav1's GEF activity upon 6-thio-GTP hydrolysis because of the accumulation of 6-thio-GDP-loaded Rac proteins, which Vav1 cannot convert to Rac-GTP (Tiede et al, 2003;Poppe et al, 2006). Furthermore, metastasis in a pancreatic cancer mouse model was shown to be inhibited with azathioprine through inhibition of the activity of Vav1 as a GEF towards Rac1 (Razidlo et al, 2015). Taken together, our results support the conclusion that the activity of Vav1 as a GEF for Rac1 is critical for the enhancement and maintaining of ADM generation.…”

Dual Targeting of Mesenchymal and Amoeboid Motility Hinders Metastatic Behavior

“…Furthermore, the small molecule compound EHop-016, which efficiently blocks the interaction of Rac1 with VAV2 (42), did not cause an additive effect on Rac1 inhibition when given to siNEDD9 cells, suggesting that NEDD9 and VAV2 share the same pathway to Rac1 activation. The potential clinical application of this compound has yet to be determined, however another VAV-family targeting drug, the purine analogue azathioprine, was recently found to inhibit pancreatic cancer metastasis (50). Additionally, overexpression of NEDD9 increased Rac1 activity, which was abrogated upon depletion of VAV2, supporting that NEDD9’s influence on Rac1 activation is VAV2-dependent.…”