When proteases reshape barriers: Basement membrane remodelling in development, wound healing and tumour progression

Basement membranes (BMs) are dynamic extracellular matrices whose remodelling controls tissue morphogenesis, regeneration and malignant progression. This review examines how a shared protease- and extracellular matrix (ECM)-based machinery reshapes laminin- and collagen IV-rich BMs during development and wound repair, and how the altered levels, localisation and regulation of these components drive cancer invasion. In development, patterned BM thinning, perforation and stiffening driven by MMPs, MT-MMPs, ADAMTS proteases and nonproteolytic regulators generate gradients that guide branching, tissue elongation and axis formation. In cutaneous wound healing, many of the same proteases (including MMP-1, MMP-9, MT1-MMP, stromelysins, serine proteases and cathepsins) act in transient, spatially restricted patterns so that keratinocytes remodel a provisional matrix at the wound edge and then rebuild a mature dermal-epidermal BM. By contrast, in carcinomas, invadopodia enriched in MT1-MMP, MMP-2, MMP-9 and related proteases concentrate pericellular proteolysis to perforate BMs, while collagen IV 'escape tracks' and laminin-derived cryptic fragments promote proliferation, survival, epithelial-mesenchymal transition and angiogenesis. Finally, we highlight emerging therapeutic strategies, including isoform- and site-selective protease inhibitors and protease-responsive or protease-modulating biomaterials, that seek to locally rebalance this protease-ECM programme to restore BM integrity in chronic wounds and limit invasive growth in cancer.