Proteases have long been associated with cancer progression, due to their ability to facilitate invasion upon matrix remodelling. However, proteases are not simply degraders of the matrix, but also play fundamental roles in modulating cellular behaviour through the proteolytic processing of specific substrates. Indeed, proteases can elicit both pro- and anti- tumorigenic effects depending on context. Using a heterocellular spheroid model of breast cancer progression, we demonstrate the repressive function of myoepithelial ADAMTS3, with its loss directing myoepithelial-led invasion of luminal cells through a physiologically relevant matrix. Degradomic analysis, using terminal amine isotopic labelling of substrates (TAILS), combined with functional assays, implicate ADAMTS3 as a mediator of fibronectin degradation. We show further that loss of ADAMTS3 enhances levels of fibronectin in the microenvironment, promoting invasion through canonical integrin α5β1 activation. Our data highlight a tumour suppressive role for ADAMTS3 in early stage breast cancer, and contribute to the growing evidence that proteases can restrain cancer progression.

长期以来，蛋白酶一直与癌症进展相关，因为它们能够促进基质重塑时的侵袭。然而，蛋白酶不仅仅是基质的降解剂，而且还通过特定底物的蛋白水解加工在调节细胞行为中发挥重要作用。事实上，根据具体情况，蛋白酶可以引发促肿瘤作用和抗肿瘤作用。使用乳腺癌进展的异细胞球体模型，我们证明了肌上皮 ADAMTS3 的抑制功能，其丧失通过生理相关基质引导肌上皮主导的管腔细胞侵袭。使用底物末端胺同位素标记 (TAILS) 进行的降解组学分析与功能测定相结合，表明 ADAMTS3 是纤连蛋白降解的介体。我们进一步表明，ADAMTS3 的缺失会增强微环境中纤连蛋白的水平，通过经典整合素 α5β1 激活促进侵袭。我们的数据强调了 ADAMTS3 在早期乳腺癌中的肿瘤抑制作用，并为越来越多的证据表明蛋白酶可以抑制癌症进展做出了贡献。