Melanoma-derived small extracellular vesicles induce lymphangiogenesis and metastasis through an NGFR-dependent mechanism

Susana García-Silva, Alberto Benito-Martín, Laura Nogués, Alberto Hernández-Barranco, Marina S. Mazariegos, Vanesa Santos, Marta Hergueta-Redondo, Pilar Ximénez-Embún, Raghu P. Kataru, Ana Amor Lopez, Cristina Merino, Sara Sánchez-Redondo, Osvaldo Graña-Castro, Irina Matei, José Ángel Nicolás-Avila, Raúl Torres-Ruiz, Sandra Rodríguez-Perales, Lola Martínez, Manuel Pérez-Martínez, Gadea MataAnna Szumera-Ciećkiewicz, Iwona Kalinowska, Annalisa Saltari, Julia M. Martínez-Gómez, Sabrina A. Hogan, H. Uri Saragovi, Sagrario Ortega, Carmen Garcia-Martin, Jasminka Boskovic, Mitchell P. Levesque, Piotr Rutkowski, Andrés Hidalgo, Javier Muñoz, Diego Megías, Babak J. Mehrara, David Lyden, Héctor Peinado

Research output: Contribution to journalArticlepeer-review

76 Scopus citations

Abstract

Secreted extracellular vesicles (EVs) influence the tumor microenvironment and promote distal metastasis. Here we analyzed the involvement of melanoma-secreted EVs in lymph node pre-metastatic niche formation in murine models. We found that small EVs (sEVs) derived from metastatic melanoma cell lines were enriched in nerve growth factor (NGF) receptor (NGFR, p75NTR), spread through the lymphatic system and were taken up by lymphatic endothelial cells, reinforcing lymph node metastasis. Remarkably, sEVs enhanced lymphangiogenesis and tumor cell adhesion by inducing ERK kinase, nuclear factor (NF)-κB activation and intracellular adhesion molecule (ICAM)-1 expression in lymphatic endothelial cells. Importantly, ablation or inhibition of NGFR in sEVs reversed the lymphangiogenic phenotype, decreased lymph node metastasis and extended survival in pre-clinical models. Furthermore, NGFR expression was augmented in human lymph node metastases relative to that in matched primary tumors, and the frequency of NGFR+ metastatic melanoma cells in lymph nodes correlated with patient survival. In summary, we found that NGFR is secreted in melanoma-derived sEVs, reinforcing lymph node pre-metastatic niche formation and metastasis.

Original languageEnglish
Pages (from-to)1387-1405
Number of pages19
JournalNature Cancer
Volume2
Issue number12
DOIs
StatePublished - Dec 2021
Externally publishedYes

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