Updated project metadata. Interactions between cells and the extracellular matrix, mediated by integrin adhesion complexes (IACs), play key roles in cancer progression and metastasis. We report here systems-level changes in the adhesome during progression of a patient-derived cutaneous squamous cell carcinoma (cSCC). We found that the actin regulatory protein Mena is enriched in IACs in metastatic cSCC cells and is connected within a subnetwork of actin-binding proteins to the LINC complex component nesprin-2.