Melanoma-derived small extracellular vesicles induce lymphangiogenesis and metastasis through an NGFR-dependent mechanism
| Autor: | Alberto Benito-Martin, David Lyden, Laura Nogués, Cristina Merino, Mitchell P. Levesque, Anna Szumera-Ciećkiewicz, Manuel Pérez-Martínez, Javier Munoz, Jasminka Boskovic, Ana Amor López, Irina Matei, Iwona Kalinowska, Lola Martínez, Carmen García-Martín, Babak J. Mehrara, Julia M. Martinez-Gomez, Vanesa Santos, Sagrario Ortega, Sara Sánchez-Redondo, Andrés Hidalgo, Diego Megías, Marina S. Mazariegos, José Ángel Nicolás-Ávila, Annalisa Saltari, Susana García-Silva, Sandra Rodriguez-Perales, Raúl Torres-Ruiz, Sabrina A. Hogan, Héctor Peinado, H. Uri Saragovi, Alberto Hernández-Barranco, Gadea Mata, Piotr Rutkowski, Pilar Ximénez-Embún, Raghu P. Kataru, Marta Hergueta-Redondo, Osvaldo Graña-Castro |
|---|---|
| Přispěvatelé: | Starr Cancer Consortium, National Institutes of Health (Estados Unidos), Paduano Foundation, Children s Cancer and Blood Foundation, Melanoma Research Alliance, Feldstein Foundation, Fundación Ramón Areces, Fundación La Caixa, Atresmedia, Asociación Española Contra el Cáncer, Malcolm Hewitt Wiener Foundation, Fifth District AHEPA Cancer Research Foundation, Hartwell Foundation and the Manning Foundation, Translational Network for the Clinical Application of Extracellular Vesicles (TeNTaCLES), Centro Nacional de Investigaciones Oncológicas Carlos III (España), Fundación AXA, Ministerio de Ciencia e Innovación. Centro de Excelencia Severo Ochoa (España) |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Cancer Research
government.form_of_government Nerve Tissue Proteins Receptors Nerve Growth Factor Metastasis Extracellular Vesicles Mice medicine Tumor Microenvironment Animals Humans Lymphangiogenesis Lymph node Melanoma Tumor microenvironment Chemistry Endothelial Cells medicine.disease Lymphatic Endothelium medicine.anatomical_structure Lymphatic system Oncology Lymphatic Metastasis government Cancer research Lymph |
| Zdroj: | Repisalud Instituto de Salud Carlos III (ISCIII) |
| Popis: | 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. we apologize to those authors whose work could not be cited due to size restrictions. We thank M. S. Soengas and the members of her laboratory for melanoma cells, primary melanocyte preparations and helpful discussions. We thank M. Detmar and S. Proulx for the mouse B16-F1R2 cell line. We are grateful to M. Yañez-Mo and M. Valés for antibodies against sEV markers. We thank D. Grela and A. Escobar from IESMAT for their support with the Zetasizer analysis. We thank G. Roncador, L. Maestre and J. L. Martinez Torrecuadrada for their help with the development and characterization of anti-NGFR antibodies and C. Villarroya Beltri for her help in flow cytometry analysis. This work was funded by the Starr Cancer Consortium (B.J.M., D.L. and H.P.), the US NIH (R01-CA169416), the Nancy C. and Daniel P. Paduano Foundation, the Children’s Cancer and Blood Foundation (H.P. and D.L.), the Melanoma Research Alliance, the Feldstein Foundation, RETOS SAF2017-82924-R (AEI/10.13039/501100011033/FEDER-UE), the Fundación Ramón Areces, the Fundación Bancaria ‘la Caixa’ (HR18-00256), ATRES-MEDIA AXA Foundation (CONSTANTES Y VITALES, una iniciativa de laSexta y Fundación AXA) and the Fundación Científica AECC (LABAE19027PEIN, GCB15152978SOEN-HP) (H.P.), the Malcolm Hewitt Wiener Foundation, the AHEPA Fifth District Cancer Research Foundation, the Hartwell Foundation and the Manning Foundation (D.L.). We are also grateful for the support of the Translational Network for the Clinical Application of Extracellular Vesicles (TeNTaCLES), RED2018-102411-T (AEI/10.13039/501100011033), the Ramón y Cajal Programme, the FERO Foundation, Comunidad of Madrid 2017-T2/BMD6026 (L.N.) and La Caixa Foundation (ID100010434, fellowship LCF/BQ/ES17/11600007) (A.H.-B.). The CNIO, certified as a Severo Ochoa Excellence Centre, is supported by the Spanish government through the ISCIII. No |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|