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 hMENA Delta v6, which have opposite functions in cell invasiveness. Their mechanisms of action have remained unclear. Here we report two major findings: (i) hMENA regulates beta 1 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 beta 1 integrin. (ii) hMENA(11a) reduces and hMENA Delta v6 increases beta 1 integrin activation and signaling. Moreover, exogenous expression of hMENA(11a) in hMENA Delta v6-positive cancer cells dramatically reduces secretion of extracellular matrix (ECM) components, including beta 1 integrin ligands and metalloproteinases. On the other hand, overexpression of the pro-invasive hMENA.v6 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 hMENA Delta v6 in the druggable beta 1 integrin-ECM signaling axis and allow stratification of patient risk, guiding their clinical management.