Inactivation of EMILIN-1 by proteolysis and secretion in small extracellular vesicles favors melanoma progression and metastasis

Several studies have demonstrated that melanoma-derived extracellular vesicles (EVs) are involved in lymph node metastasis; however, the molecular mechanisms involved are not defined completely. Here, we found that EMILIN-1 is proteolyzed and secreted in small EVs (sEVs) as a novel mechanism to reduce its intracellular levels favoring metastasis in lymph node metastatic cells. Interestingly, we observed that EMILIN-1 has intrinsic tumor and metastasis suppressive-like properties reducing effective migration, cell viability, primary tumor growth and metastasis in mouse melanoma models. Finally, analysis in human melanoma samples showed that tumor cells with high levels of EMILIN-1 are reduced in metastatic lesions compared to primary tumors or nevi. Overall, our analysis suggests that the inactivation of EMILIN-1 by proteolysis and secretion in sEVs reduce its intrinsic tumor suppressive activities in melanoma favoring tumor progression and metastasis.