Tumor-associated factors are enriched in lymphatic exudate compared to plasma in metastatic melanoma patients

J Exp Med. 2019 May 6;216(5):1091-1107. doi: 10.1084/jem.20181618. Epub 2019 Apr 11.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers, Tumor / analysis
  • Cell Line, Tumor
  • Cytokines / analysis
  • Exosomes / metabolism
  • Extracellular Vesicles / metabolism
  • Exudates and Transudates / metabolism*
  • Humans
  • Lymph / metabolism*
  • Lymph Node Excision
  • Lymphatic Metastasis
  • Lymphatic Vessels / metabolism*
  • Melanoma / blood*
  • Melanoma / pathology*
  • Melanoma / secondary
  • Melanoma / surgery
  • Mice
  • Mice, Inbred C57BL
  • MicroRNAs / analysis
  • Proteomics / methods
  • S100 Proteins / analysis
  • Skin Neoplasms / blood*
  • Skin Neoplasms / pathology*
  • Skin Neoplasms / secondary
  • Skin Neoplasms / surgery


  • Biomarkers, Tumor
  • Cytokines
  • MicroRNAs
  • S100 Proteins