García-Silva Susana, Benito-Martín Alberto, Nogués Laura, Hernández-Barranco Alberto, Mazariegos Marina S, Santos Vanesa, Hergueta-Redondo Marta, Ximénez-Embún Pilar, Kataru Raghu P, Lopez Ana Amor, Merino Cristina, Sánchez-Redondo Sara, Graña-Castro Osvaldo, Matei Irina, Nicolás-Avila José Ángel, Torres-Ruiz Raúl, Rodríguez-Perales Sandra, Martínez Lola, Pérez-Martínez Manuel, Mata Gadea, Szumera-Ciećkiewicz Anna, Kalinowska Iwona, Saltari Annalisa, Martínez-Gómez Julia M, Hogan Sabrina A, Saragovi H Uri, Ortega Sagrario, Garcia-Martin Carmen, Boskovic Jasminka, Levesque Mitchell P, Rutkowski Piotr, Hidalgo Andrés, Muñoz Javier, Megías Diego, Mehrara Babak J, Lyden David, Peinado Héctor
Microenvironment and Metastasis Laboratory, Molecular Oncology Programme, Spanish National Cancer Research Center (CNIO), Madrid, Spain.
Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics and Cell and Developmental Biology, Weill Cornell Medical College, New York, NY, USA.
Nat Cancer. 2021 Dec;2(12):1387-1405. doi: 10.1038/s43018-021-00272-y. Epub 2021 Nov 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 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.
分泌型细胞外囊泡（EVs）影响肿瘤微环境并促进远处转移。在此，我们分析了黑色素瘤分泌的EVs在小鼠模型中淋巴结前转移微环境形成中的作用。我们发现，源自转移性黑色素瘤细胞系的小细胞外囊泡（sEVs）富含神经生长因子受体（NGFR，p75NTR），通过淋巴系统传播并被淋巴管内皮细胞摄取，从而增强淋巴结转移。值得注意的是，sEVs通过诱导淋巴管内皮细胞中的ERK激酶、核因子（NF）-κB活化和细胞间黏附分子（ICAM）-1表达来增强淋巴管生成和肿瘤细胞黏附。重要的是，在临床前模型中，sEVs中NGFR的缺失或抑制可逆转淋巴管生成表型，减少淋巴结转移并延长生存期。此外，相对于匹配的原发性肿瘤，人淋巴结转移中NGFR表达增加，且淋巴结中NGFR转移性黑色素瘤细胞的频率与患者生存率相关。总之，我们发现NGFR在黑色素瘤来源的sEVs中分泌，增强淋巴结前转移微环境的形成和转移。
