Fibroblast-mediated proteolytic cleavage of ECM proteins requires direct contact with tumor cells or binding of HNSCC secreted endothelin-1 (ET-1), leading to localization of adisintegrin and metalloprotease (ADAM)-12 and ADAM-17 at fibroblast podosomes, followed by secretion and activation of MMP-2 and MMP-9 from carcinoma cells and CAFs [34,152,153,154]. The gene discussed is MMP9; the disease is head and neck squamous cell carcinoma.