Invadopodia are protrusive structures used by
tumor cells for degradation of the extracellular matrix to promote invasion [1]. Invadopodia formation and function are regulated by cytoskeletal-remodeling pathways and the oncogenic
kinase Src. The
guanine nucleotide exchange factor Vav1, which is an activator of Rho family
GTPases, is ectopically expressed in many
pancreatic cancers, where it promotes
tumor cell survival and migration [2, 3]. We have now determined that Vav1 is also a potent regulator of matrix degradation by pancreatic
tumor cells as depletion of Vav1 by
siRNA-mediated knockdown inhibits the formation of invadopodia. This requires the exchange function of Vav1 toward the
GTPase Cdc42, which is required for invadopodia assembly [4, 5]. In addition, we have determined that Src-mediated phosphorylation and activation of Vav1 are both required for, and, unexpectedly, sufficient for, invadopodia formation. Expression of Vav1 Y174F, which mimics its activated state, is a potent inducer of invadopodia formation through Cdc42, even in the absence of Src activation and phosphorylation of other Src substrates, such as
cortactin. Thus, these data identify a novel mechanism by which Vav1 can enhance the tumorigenicity and invasive potential of
cancer cells. These data suggest that Vav1 promotes the matrix-degrading processes underlying
tumor cell migration and further, under conditions of ectopic Vav1 expression, that Vav1 is a central regulator and major driver of invasive matrix remodeling by pancreatic
tumor cells.