Cancer-associated fibroblast ADAM17 mediates a feed-forward loop promoting cancer cell migration

Abstract

One of the ways in which cancer associated fibroblasts (CAF) influence the tumour-microenvironment (TME) is by releasing soluble factors to elicit responses in nearby cells. These factors may be released by modification of the extracellular matrix (ECM), secretion from intracellular compartments, or proteolytic cleavage from the cell surface. A major mediator of proteolytic processing of cell surface proteins is the a disintegrin and metalloproteinase (ADAM) family, commonly ADAM17. The role of ADAM17 in CAF, however, remains largely unknown. Here, we show that expression of ADAM17 was induced in normal oral fibroblasts (NOF) and CAF by exposure to oral cancer cell-derived conditioned medium and depletion of ADAM17 reduced the ability of CAF to promote cancer cell migration by negatively regulating cancer cell-associated N-cadherin. Proteomic analysis of ADAM17-depleted CAF revealed changes in the expression of pro-tumorigenic proteins, including fibroblast growth factor 2 (FGF2). Inhibition of FGF2/FGFR1 signalling abrogated the pro-migratory effects of CAF by reducing cancer cell-associated N-cadherin, an effect rescued by addition of recombinant FGF2. Taken together, these results indicate a novel molecular mechanism underpinning cancer cell migration in which tumour-derived factors induce ADAM17 expression in CAF, thus initiating a feed-forward loop wherein CAF release FGF2 to stimulate N-cadherin-dependent cancer cell migration.