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Opposing roles for ADAMTS2 and ADAMTS14 in myofibroblast differentiation and function

Crosstalk between cancer and stellate cells is pivotal in pancreatic cancer, resulting in differentiation of stellate cells into myofibroblasts that drive. To assess co-operative mechanisms in a 3D context, we generated chimeric spheroids using human and mouse cancer and stellate cells. Species-specific deconvolution of bulk-RNA sequencing data revealed cell type-specific transcriptomes underpinning invasion. This dataset highlighted stellate-specific expression of the collagen-processing enzymes ADAMTS2 and ADAMTS14. While both proteases contributed to collagen-processing, loss of ADAMTS2 reduced, while loss of ADAMTS14 promoted, myofibroblast differentiation and invasion. Proteomic analysis revealed enrichment of known, protease-specific substrates following knockdown of either protease. Functional analysis demonstrated that these two enzymes regulate myofibroblast differentiation through opposing roles in regulating transforming growth factor β availability, acting on protease-specific substrates, SERPINE2 and Fibulin2, for ADAMTS2 and ADAMTS14, respectively. Showcasing a broader complexity for these enzymes, we uncover a novel regulatory axis governing malignant behaviour of the pancreatic cancer stroma.