Revisiting laminin and extracellular matrix remodeling in metastatic squamous cell carcinoma: What have we learned after more than four decades of research?

Patients with squamous cell carcinoma (SCC) have significantly lower survival upon the development of distant metastases. The extracellular matrix (ECM) is a consistent yet dynamic influence on the metastatic capacity of SCCs. The ECM encompasses a milieu of structural proteins, signaling molecules, and enzymes. Just over 40 years ago, the fibrous ECM glycoprotein laminin was identified. Roughly four decades of research have revealed a pivotal role of laminins in metastasis. However, trends in ECM alterations in some cancers have been applied broadly to all metastatic diseases, despite evidence that these characteristics vary by tumor type. We will summarize how laminins influence the SCC metastatic process exclusively. Enhanced laminin protein deposition occurs at the invasive edge of SCC tumors, which correlates with elevated levels of laminin-binding β1 integrins on SCC cells, increased MMP-3 presence, worse prognosis, and lymphatic dissemination. Although these findings are significant, gaps in knowledge of the formation of a premetastatic niche, the processes of intra- and extravasation, and the contributions of the ECM to SCC metastatic cell dormancy persist. Bridging these gaps requires novel in vitro systems and animal models that reproduce tumor-stromal interactions and spontaneous metastasis seen in the clinic. These advances will allow accurate assessment of laminins to predict responders to transforming growth factor-β inhibitors and immunotherapy, as well as potential combinatorial therapies with the standard of care. Such clinical interventions may drastically improve quality of life and patient survival by explicitly targeting SCC metastasis.