Fig. 4. ECM remodelling in the metastatic cascade.

a Angiogenesis and high MMP activity at the primary tumour site lead to a disrupted vasculature that allows tumour cells to intravasate and enter the circulation. Circulating tumour cells (CTCs) may secrete ECM that protects them from immune surveillance. b CTCs may connect via matrix-like interactions with neutrophil extracellular traps (NETs) and NETotic neutrophils using integrins that are expressed on CTCs and neutrophils. c Endothelial cells (EC) deposit and assemble fibrillar fibronectin that promotes the attachment of CTCs to the endothelial wall at distant organs. Increased MMP activity creates a leaky vasculature allowing CTCs to extravasate into the surrounding tissue. ECs also remodel the tissue in distant organs and deposit ECM contributing to the establishment of a pre-metastatic niche. d Various factors derived from the primary tumour such as growth factors, MMPs, LOX, ECM proteins like fibronectin, and exosomes, create a pre-metastatic niche at a distant site to prime the new tissue for metastasis. Stromal cells in the pre-metastatic niche are activated by tumour-derived factors and myofibroblasts remodel the ECM, for example, by the deposition of fibronectin, tenascin C, osteopontin, and versican depending on tissue context. Bone marrow-derived cells (BMDCs) are recruited to the pre-metastatic niche, attach to the remodelled ECM via integrins and contribute to further ECM remodelling in preparation for the arrival of disseminated tumour cells. e CTCs that extravasate through the disrupted vasculature into the distant tissue may become dormant. Proteases expressed in NETs including neutrophil elastase and MMP-9 cleave laminin, generating a specific matrikine that can awaken dormant tumour cells. Together, these ECM remodelling processes support the formation of metastasis.