Fig. 1: Mechanisms of ECM remodelling.

a ECM deposition and modification: using collagen as an example, pre-procollagen is synthesised and translocated to the Golgi, where it becomes a procollagen α-chain. This procollagen molecule undergoes several post-translational modifications (PTMs) to modify its properties. The PTMs include glycosylation, pro-peptide alignment, disulphide bond formation and hydroxylation. Lysine hydroxylation of the procollagen chains by PLODs allows for spontaneous triple helix formation within the cell and secretion into the extracellular space. Here, the pro-peptides on the C- and N-terminal are cleaved by proteases creating collagen fibrils. For further collagen fibre assembly, collagens fibrils are cross-linked by LOX. b ECM degradation: proteases including MMPs cleave the ECM proteins, which releases matrix-bound growth factors (GFs) and cytokines, and ECM fragments, including matrikines and also remove barriers for cell migration. c Force-mediated ECM remodelling: integrin binding to the ECM molecules applies forces to ECM molecules. This can change the conformation of the ECM molecule, thereby exposing binding sites to support self-assembly into fibrils that induces fibre alignment. The mechanical force applied by the integrins in this modification process can also cause non-proteolytic breaching of the basement membrane that will allow cancer cell invasion.