Identifying cancer biomarkers is of great interest for patient prognosis and monitoring.,However, tumor-associated factors are diluted in blood and challenging to detect.,Broggi et al. show that lymphatic exudate, accessible at the time of lymphadenectomy, is highly enriched in tumor-associated factors and therefore a promising source for biomarker discovery.,Liquid biopsies allow monitoring of cancer progression and detection of relapse, but reliable biomarkers in melanoma are lacking.,Because secreted factors preferentially drain to lymphatic vessels before dilution in the blood, we hypothesized that lymph should be vastly enriched in cancer biomarkers.,We characterized postoperative lymphatic exudate and plasma of metastatic melanoma patients after lymphadenectomy and found a dramatic enrichment in lymphatic exudate of tumor-derived factors and especially extracellular vesicles containing melanoma-associated proteins and miRNAs, with unique protein signatures reflecting early versus advanced metastatic spread.,Furthermore, lymphatic exudate was enriched in memory T cells, including tumor-reactive CD137+ and stem cell-like types.,In mice, lymph vessels were the major route of extracellular vesicle transport from tumors to the systemic circulation.,We suggest that lymphatic exudate provides a rich source of tumor-derived factors for enabling the discovery of novel biomarkers that may reflect disease stage and therapeutic response.
García-Silva et al. show for the first time that extracellular vesicles isolated from the exudative seroma obtained from the lymphatic drainage implanted in melanoma patients after lymphadenectomy can be interrogated for melanoma markers and BRAF mutations.,Profiling the BRAFV600E mutation in this biofluid is a novel approach to predict disease relapse.,Liquid biopsies from cancer patients have the potential to improve diagnosis and prognosis.,The assessment of surrogate markers of tumor progression in circulating extracellular vesicles could be a powerful non-invasive approach in this setting.,We have characterized extracellular vesicles purified from the lymphatic drainage also known as exudative seroma (ES) of stage III melanoma patients obtained after lymphadenectomy.,Proteomic analysis showed that seroma-derived exosomes are enriched in proteins resembling melanoma progression.,In addition, we found that the BRAFV600E mutation can be detected in ES-derived extracellular vesicles and its detection correlated with patients at risk of relapse.