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Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Bioquímica. Fecha de lectura: 13-12-2019, Esta tesis tiene embargado el acceso al texto completo hasta el 13-06-2021, It has been described that melanoma-derived exosomes have a role in lymph node metastasis reinforcing lymphangiogenesis and extracellular matrix remodeling. Several studies have demonstrated that melanoma-derived exosomes home in sentinel lymph nodes promoting gene expression changes that favor metastasis. Recent data from our laboratory support a role for melanoma-derived exosomes in establishing the lymph node pre-metastatic niche formation due to specific cargo. In this thesis, we postulated that lymph node microenvironment acts as a selective pressure selecting specific phenotypes for metastasis. As such, we wanted to analyze if lymph node metastatic melanoma cells present a specific signature that may favor their survival in lymph nodes. In our analysis, we have found a specific signature of genes over-expressed and proteins hyper-secreted in exosomes from a mouse melanoma lymph node metastatic model. Out of these candidates, EMILIN1 was selected due to its relevance in lymphatic vessel functionality. We have found that EMILIN1 impacts negatively on cell proliferation and migration of melanoma cells. Overall, our data support that EMILIN1 acts as a tumour suppressor-like protein both intrinsically and extrinsically and its function is inactivated by its degradation and secretion in exosomes. Importantly, our in vivo studies demonstrate that its overexpression reduced primary tumour growth and metastasis in mouse melanoma models. Analysis in human melanoma showed that its expression is maintained along melanoma progression but cells expressing high levels of EMILIN1 are reduced in metastatic lesions. Overall, our analysis suggests a novel mechanism involved in the inactivation of EMILIN1 in melanoma favouring tumour progression., This work was supported by the following grants and fellowships: - Beca Excelencia Severo Ochoa PhD Fellowship, 2014 call- Ana Isabel Amor López. Ministerio de Ciencia, Innovación y Universidades. - Proyecto GRUPOS COORDINADOS ESTABLES DE INVESTIGACIÓN, Asociación Española contra el cáncer (AECC). SAF2014 54541-R. MINECO