We have previously demonstrated that the expression of MMPs, MT-MMPs and integrins in human melanoma cell lines is differentially regulated depending on the type and assembly state of the extracellular matrix on which the cells are seeded. We examined differential gene expression over time as the human melanoma cell line VMM 5 degraded and contracted collagen lattices. We observed a correlation of ADAM 9 expression with the organizational state of the extracellular matrix. ADAM 9 is downregulated on organized matrix, as represented in our model system by growth in a collagen lattice compared with growth as a monolayer on unorganized matrix represented by gelatin or other single matrix components. This regulation is the opposite of that previously observed for MT1-MMP and MMP-9. ADAM 10, another proteolytically active reprolysin, showed a similar tendency. As the collagen lattice is contracted over time, upregulation of ADAM 10 occurs, which is the opposite of the regulation observed for MT1-MMP and MMP-2. Other proteins of interest, which were shown to be differentially expressed on the basis of matrix state, include TIMP 3, cadherin F1B1, and plasminogen activator inhibitor-1. The results of this study suggest a role for ADAM 9 and ADAM 10 in the invasion and migration of melanoma with their expression dependent on the organizational state of the matrix with which the cells are interacting.