Understanding how cancer cells survive, invade and migrate is of fundamental importance to the development of approaches to inhibit invasion and metastasis in patients. Proteins recruited at adhesion complexes, known as the adhesome, are involved in multiple mechanisms which control cancer cell behaviour. Here, we used a proteomic and network analysis approach to perform a global assessment of functional molecular units associated with cancer cell progression in the context of the adhesome. We present the functional modules of the adhesome at different stages of human cutaneous squamous cell carcinoma (SCC) progression. From the network analysis, we found that exportin-1, a mediator of protein export from the nucleus to the cytoplasm, is an important hub during cancer progression. Interestingly, one of the interactors of exportin-1 is the actin-regulator Mena. We found that Mena has a nuclear function in metastatic SCC cells and that the nucleocytoplasmic shuttling of Mena is regulated by integrin activation and focal adhesion kinase (FAK). Moreover, our preliminary results suggest that Mena may act as a molecular clutch for the mechanosensing function of Nesprin-2 with actin. The putative molecular clutch activity of Mena regulates the phosphorylation of EMERIN and possibly affects histone methylation. Here, we propose a novel mechanism by which Mena may regulate metastasis during SCC progression.