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00925njm 22002777a 4500 dc García-Silva, Susana author Benito-Martín, Alberto author Nogués, Laura author Hernández-Barranco, Alberto author Mazariegos, Marina S. author Santos, Vanesa author Hergueta-Redondo, Marta author Ximénez-Embún, Pilar author Kataru, Raghu P. author Lopez, Ana Amor author Merino, Cristina author Sánchez-Redondo, Sara author Graña-Castro, Osvaldo author Matei, Irina author Nicolás-Avila, José Ángel author Torres-Ruiz, Raúl author Rodríguez-Perales, Sandra author Martinez, Lola author Pérez-Martínez, Manuel author Mata, Gadea author Szumera-Ciećkiewicz, Anna author Kalinowska, Iwona author Saltari, Annalisa author Martínez-Gómez, Julia M. author Hogan, Sabrina A. author Saragovi, H. Uri author Ortega, Sagrario author Garcia-Martin, Carmen author Boskovic, Jasminka author Levesque, Mitchell P. author Rutkowski, Piotr author Hidalgo, Andres author Muñoz, Javier author Megias Vazquez, Diego author Mehrara, Babak J. author Lyden, David author Peinado Selgas, Hector author 2021-11-25 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. Nat Cancer. 2021; http://hdl.handle.net/20.500.12105/13494 10.1038/s43018-021-00272-y 2662-1347 Nature Cancer Melanoma-derived small extracellular vesicles induce lymphangiogenesis and metastasis through an NGFR-dependent mechanism