Tethered exosomes containing MT1-MMP contribute to extracellular matrix degradation during breast cancer progression

Abstract

For cancer cells to escape from the primary tumor and metastasize, they must degrade and navigate through the extracellular matrix (ECM). The transmembrane protease MT1-MMP plays a key role in localized matrix degradation, and its overexpression promotes cancer invasion. In this study, we demonstrate that MT1- MMP is trafficked to the intraluminal vesicles of multivesicular endosomes, and subsequently released from cells on exosomes, a subtype of extracellular vesicle that can be retained to the surface of the originating cell by the anti-viral restriction factor, tetherin. While tetherin overexpression is linked to increased cell migration and invasion in various cancers, its role in these processes remains unclear. Our findings reveal that expression of tetherin by breast cancer cells promotes the retention of MT1-MMP-positive exosomes at their cell surface, while tetherin loss enhances exosome escape and impairs ECM degradation. Thus, tethered exosomes promote the retention of MT1-MMP at the surface of cells, aiding the degradation of the ECM and promoting cancer cell invasion.