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.

中文翻译：

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ADAMTS2 和 ADAMTS14 在肌成纤维细胞分化和功能中的相反作用

癌症和星状细胞之间的串扰是胰腺癌的关键，导致星状细胞分化为驱动肌成纤维细胞。为了评估 3D 环境中的合作机制，我们使用人类和小鼠癌症以及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细胞类型特异性转录组支持入侵。该数据集突出了胶原加工酶 ADAMTS2 和 ADAMTS14 的星状特异性表达。虽然两种蛋白酶都有助于胶原蛋白的加工，但 ADAMTS2 的缺失减少了，而 ADAMTS14 的缺失促进了肌成纤维细胞的分化和侵袭。蛋白质组学分析揭示了在任一蛋白酶敲低后已知的蛋白酶特异性底物的富集。功能分析表明，这两种酶通过在调节转化生长因子 β 可用性方面的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 SERPINE2 和 Fibulin2。展示了这些酶的更广泛的复杂性，我们发现了一个新的调节轴来控制胰腺癌基质的恶性行为。