hMENA isoforms impact NSCLC patient outcome through fibronectin/β1 integrin axis

We demonstrated previously that the splicing of the actin regulator, hMENA, generates two alternatively expressed isoforms, hMENA^11a and hMENAΔv6, which have opposite functions in cell invasiveness. Their mechanisms of action have remained unclear. Here we report two major findings: (i) hMENA regulates β1 integrin expression. This was shown by depleting total hMENA, which led to loss of nuclear expression of serum response factor (SRF)-coactivator myocardin-related transcription factor 1 (MRTF-A), leading to an increase in the G-actin/F-actin ratio crucial for MRTF-A localization. This in turn inhibited SRF activity and the expression of its target gene β1 integrin. (ii) hMENA^11a reduces and hMENAΔv6 increases β1 integrin activation and signaling. Moreover, exogenous expression of hMENA^11a in hMENAΔv6-positive cancer cells dramatically reduces secretion of extracellular matrix (ECM) components, including β1 integrin ligands and metalloproteinases. On the other hand, overexpression of the pro-invasive hMENAΔv6 increases fibronectin production. In primary tumors high hMENA^11a correlates with low stromal fibronectin and a favorable clinical outcome of early node-negative non-small-cell lung cancer patients. These data provide new insights into the roles of hMENA^11a and hMENAΔv6 in the druggable β1 integrin-ECM signaling axis and allow stratification of patient risk, guiding their clinical management.