In melanoma, invasion through the extracellular matrix (ECM) is a harbinger of dissemination and mortality. We find that changes in ECM composition of invasive human melanoma specimens resemble changes found during skin wound healing. Most highly upregulated in invasive melanoma was Tenascin C (TN‐C). Simultaneously, the matrix proteoglycans decorin and lumican were downregulated and the level of collagen I was decreased as the dermal matrix became ‘less mature’. The cellular origin of these matrix changes are not fully settled; still the melanoma cell lines, derived from tumors of different stages, express varied increased levels of TN‐C and fibronectin and decreased levels of collagen I compared to normal human melanocytes. Cells expressing higher amounts of TN‐C migrate faster in wound healing assays; on TN‐C pre‐coated surfaces both melanoma cells and normal melanocytes increase migration. Our group previously showed that the EGF‐like repeats of TN‐C are able to bind the EGFR with μM affinity and preferentially activate the motogenic signaling cascades. This upregulation of EGFR‐activating TN‐C is concomitant with downregulation of decorin and lumican, which have been reported to dampen EGFR signaling. Therefore, we hypothesize that the increased levels of TN‐C in melanomas promote tumor cell migration and invasion heralding dissemination through enhanced EGFR signaling.Funding: Internal (AW).