癌症和星状细胞之间的串扰在胰腺癌中至关重要，导致星状细胞分化为肌成纤维细胞，从而驱动肿瘤进展。为了评估 3D 背景下的合作机制，我们使用人类和小鼠癌症和星状细胞生成了嵌合球体。大量 RNA 测序数据的物种特异性反卷积揭示了支持入侵的细胞类型特异性转录组。该数据集突出显示了编码胶原加工酶 ADAMTS2 和 ADAMTS14 的转录本的星状特异性表达。引人注目的是，ADAMTS2 的缺失减少了肌成纤维细胞的分化和侵袭，而 ADAMTS14 的缺失则促进了肌成纤维细胞的分化和侵袭，而与它们在胶原蛋白加工中的主要作用无关。功能和蛋白质组学分析表明，这两种酶通过在调节转化生长因子 β 可用性方面发挥相反作用来调节肌成纤维细胞分化，分别作用于 ADAMTS2 和 ADAMTS14 的蛋白酶特异性底物 Serpin E2 和 fibulin 2。我们展示了这些酶的更广泛的复杂性，发现了控制胰腺癌基质恶性行为的新调控轴。 © 2023 作者。约翰·威利出版的《病理学杂志》

Crosstalk between cancer and stellate cells is pivotal in pancreatic cancer, resulting in differentiation of stellate cells into myofibroblasts that drives tumour progression. To assess cooperative 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 transcripts encoding the collagen-processing enzymes ADAMTS2 and ADAMTS14. Strikingly, loss of ADAMTS2 reduced, while loss of ADAMTS14 promoted, myofibroblast differentiation and invasion independently of their primary role in collagen-processing. Functional and proteomic analysis demonstrated that these two enzymes regulate myofibroblast differentiation through opposing roles in the regulation of transforming growth factor β availability, acting on the protease-specific substrates, Serpin E2 and fibulin 2, for ADAMTS2 and ADAMTS14, respectively. Showcasing a broader complexity for these enzymes, we uncovered a novel regulatory axis governing malignant behaviour of the pancreatic cancer stroma. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.© 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.