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García-Silva S, Benito-Martín A, Nogués L, et al. Melanoma-derived small extracellular vesicles induce lymphangiogenesis and metastasis through an NGFR-dependent mechanism. Nat Cancer. 2021;2(12):1387-1405doi: 10.1038/s43018-021-00272-y.
García-Silva, S., Benito-Martín, A., Nogués, L., Hernández-Barranco, A., Mazariegos, M. S., Santos, V., Hergueta-Redondo, M., Ximénez-Embún, P., Kataru, R. P., Lopez, A. A., Merino, C., Sánchez-Redondo, S., Graña-Castro, O., Matei, I., Nicolás-Avila, J. �. �., Torres-Ruiz, R., Rodríguez-Perales, S., Martínez, L., Pérez-Martínez, M., Mata, G., Szumera-Ciećkiewicz, A., Kalinowska, I., Saltari, A., Martínez-Gómez, J. M., Hogan, S. A., Saragovi, H. U., Ortega, S., Garcia-Martin, C., Boskovic, J., Levesque, M. P., Rutkowski, P., Hidalgo, A., Muñoz, J., Megías, D., Mehrara, B. J., Lyden, D., & Peinado, H. (2021). Melanoma-derived small extracellular vesicles induce lymphangiogenesis and metastasis through an NGFR-dependent mechanism. Nature cancer, 2(12), 1387-1405. https://doi.org/10.1038/s43018-021-00272-y
García-Silva, Susana, et al. "Melanoma-derived small extracellular vesicles induce lymphangiogenesis and metastasis through an NGFR-dependent mechanism." Nature cancer vol. 2,12 (2021): 1387-1405. doi: https://doi.org/10.1038/s43018-021-00272-y
García-Silva S, Benito-Martín A, Nogués L, Hernández-Barranco A, Mazariegos MS, Santos V, Hergueta-Redondo M, Ximénez-Embún P, Kataru RP, Lopez AA, Merino C, Sánchez-Redondo S, Graña-Castro O, Matei I, Nicolás-Avila JÁ, Torres-Ruiz R, Rodríguez-Perales S, Martínez L, Pérez-Martínez M, Mata G, Szumera-Ciećkiewicz A, Kalinowska I, Saltari A, Martínez-Gómez JM, Hogan SA, Saragovi HU, Ortega S, Garcia-Martin C, Boskovic J, Levesque MP, Rutkowski P, Hidalgo A, Muñoz J, Megías D, Mehrara BJ, Lyden D, Peinado H. Melanoma-derived small extracellular vesicles induce lymphangiogenesis and metastasis through an NGFR-dependent mechanism. Nat Cancer. 2021 Dec;2(12):1387-1405. doi: 10.1038/s43018-021-00272-y. Epub 2021 Nov 25. PMID: 34957415; PMCID: PMC8697753.
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Nat Cancer. 2021 Dec;2(12):1387-1405. doi: 10.1038/s43018-021-00272-y. Epub 2021 Nov 25.

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

Nature cancer

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 Mata, Anna 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

Affiliations

  1. Microenvironment and Metastasis Laboratory, Molecular Oncology Programme, Spanish National Cancer Research Center (CNIO), Madrid, Spain.
  2. Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics and Cell and Developmental Biology, Weill Cornell Medical College, New York, NY, USA.
  3. Proteomics Unit - ProteoRed-ISCIII, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
  4. Department of Surgery, Plastic and Reconstructive Surgery Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  5. Bioinformatics Unit, Structural Biology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
  6. Area of Developmental and Cell Biology, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain.
  7. Molecular Cytogenetics Unit, Human Cancer Genetics Programme, Spanish National Cancer Research Center (CNIO), Madrid, Spain.
  8. Flow Cytometry Unit, Biotechnology Programme, Spanish National Cancer Research Center (CNIO), Madrid, Spain.
  9. Cofocal Microscopy Unit, Biotechnology Programme, Spanish National Cancer Research Center (CNIO), Madrid, Spain.
  10. Maria Sklodowska-Curie National Research Institute of Oncology, Department of Pathology and Laboratory Medicine, Warsaw, Poland.
  11. Institute of Hematology and Transfusion Medicine, Diagnostic Hematology Department, Warsaw, Poland.
  12. Maria Sklodowska-Curie National Research Institute of Oncology, Department of Soft Tissue/Bone Sarcoma and Melanoma, Warsaw, Poland.
  13. Department of Dermatology, University of Zurich, University of Zurich Hospital, Zurich, Switzerland.
  14. Lady Davis Institute-Jewish General Hospital, Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada.
  15. Transgenic Mice Unit, Biotechnology Programme, Spanish National Cancer Research Center (CNIO), Madrid, Spain.
  16. Electron Microscopy Unit, Spanish National Cancer Research Center (CNIO), Madrid, Spain.

PMID: 34957415 PMCID: PMC8697753 DOI: 10.1038/s43018-021-00272-y

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 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

Keywords: CD271; NGFR; cell adhesion; lymph node metastasis; lymphangiogenesis; melanoma metastasis; metastasis mechanisms; p75NTR; pre-metastatic niche formation; small extracellular vesicles

Conflict of interest statement

Competing Interests Statement The authors have no conflict of interests.

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