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The most well studied mode of cell motility for metastasizing tumor cells is chemotaxis, the directional movement of cells attracted to a source of soluble cues. In contrast, haptotaxis, migration of cells on gradients of substrate-bound factors, remains poorly understood. Due to the high expression of extracellular matrix (ECM) proteins such as collagen and fibronectin (FN) in metastatic tumors, it is possible that haptotaxis along ECM gradients could also be driving invasion. Mena, an actin regulatory protein, plays an important role in cell motility and is upregulated in various cancers, where Mena, and in particular the MenaINV isoform, potentiates chemotactic and invasive responses to EGF. All Mena isoforms bind directly to the α5 subunit of the α5β1 integrin, a FN receptor. We hypothesized that the pro-metastatic effect of MenaINV arises from increases in tumor cell responses to specific chemotactic and haptotactic …