Beyond the scaffold: extracellular matrix uptake in breast cancer

Breast cancer is associated with a highly fibrotic tumour microenvironment, where cancer-associated fibroblasts (CAFs) secrete excessive amounts of extracellular matrix (ECM). Fibrosis and collagen deposition correlate with poor patient survival, indicating that the ECM plays a role in promoting tumorigenesis. The ECM is constantly remodelled through extracellular and intracellular degradation pathways. While protease-dependent extracellular ECM degradation has been well studied, the intracellular degradation pathway is less understood. Here, I will describe the evidence supporting a role for ECM internalisation and lysosomal degradation in promoting breast cancer progression. Both cancer cells and CAFs are reported to uptake ECM components via different ECM receptors. These include TEM8 in fibroblasts, Endo180 in both cancer cells and CAFs, and α2β1 integrin in cancer cells. Importantly, this process has been associated with metabolic reprogramming under nutrient deprivation conditions representative of the breast cancer TME, cancer cell growth in vitro and in vivo, and cancer cell migration and invasion. Therefore, regulators of ECM endocytosis and lysosomal delivery might represent novel potential targets to prevent tumour growth and metastasis in ECM-rich breast cancers.