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bioRxiv · 10.1101/2022.09.20.508645

Opposing roles for ADAMTS2 and ADAMTS14 in myofibroblast differentiation and function

Carter, E. P.·Yoneten, K. K.·Gavara, N.·Tyler, E. J.·Gauthier, V.·Murray, E.·Cameron, A.·Pearce, O. M. T.·Grose, R. P.
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Abstract

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 {beta} 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.

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Carter, E. P., Yoneten, K. K., Gavara, N., Tyler, E. J., Gauthier, V., Murray, E., Cameron, A., Pearce, O. M. T., Grose, R. P.. 2022-09-20. Opposing roles for ADAMTS2 and ADAMTS14 in myofibroblast differentiation and function. https://doi.org/10.1101/2022.09.20.508645

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