Syntenin orchestrates matrix degradation by controlling MT1-MMP secretion in small extracellular vesicles and invadopodia formation

Extracellular matrix (ECM) remodelling is essential for tumour progression. The metalloproteinase MT1-MMP promotes cell invasion by degrading ECM components. MT1-MMP accumulates at invadopodia, actin-rich structures mediating ECM degradation, and is also present on the surface of small extracellular vesicles (sEV), key players in cell-to-cell communication. The role of sEV-associated MT1-MMP in ECM degradation and the mechanisms supporting MT1-MMP loading into sEV are unknown. We previously established that the syntenin PDZ protein, in association with the syndecan (SDC), is essential for sEV from endosomal origin biogenesis. In the present study, we demonstrate that syntenin contributes to ECM degradation via invadopodia in MDA-MB-231 triple negative breast cancer (TNBC) cells, whereas SDC limit it. Moreover, we identify that syntenin colocalizes with MT1-MMP in late endosomes and directly interacts with MT1-MMP. Furthermore, we decipher that both syntenin and SDC are essential for the specific loading of MT1-MMP into sEV. Additionally, we show that sEV-mediated ECM degradation depends on MT1-MMP activity and syntenin. Our findings show how syntenin-SDC-MT1-MMP complexes orchestrate ECM degradation and pave the way for innovative rational approaches to control TNBC invasion.