Extracellular vesicles secreted by triple-negative breast cancer stem cells trigger premetastatic niche remodeling and metastatic growth in the lungs
González-Callejo, Patricia (Instituto de Salud Carlos III)
Gener, Petra (Instituto de Salud Carlos III)
Díaz Riascos, Zamira Vanessa (Hospital Universitari Vall d'Hebron)
Conti, Sefora (Institut de Bioenginyeria de Catalunya)
Cámara-Sánchez, Patricia (Hospital Universitari Vall d'Hebron)
Riera Brillas, Roger (Department of Biomedical Engineering. Eindhoven University of Technology)
Mancilla, Sandra (Hospital Universitari Vall d'Hebron)
García-Gabilondo, Miguel (Hospital Universitari Vall d'Hebron)
Peg, Vicente (Centro de Investigación Biomédica en Red de Cáncer)
Arango, Diego (Hospital Universitari Vall d'Hebron)
Rosell Novel, Anna (Hospital Universitari Vall d'Hebron)
Labernadie, Anna (Institut de Bioenginyeria de Catalunya)
Trepat, Xavier (Institució Catalana de Recerca i Estudis Avançats)
Albertazzi, Lorenzo (Department of Biomedical Engineering. Eindhoven University of Technology)
Schwartz, S. (Instituto de Salud Carlos III)
Seras-Franzoso, Joaquin (Universitat Autònoma de Barcelona. Departament de Genètica i de Microbiologia)
Abasolo, Ibane (Hospital Universitari Vall d'Hebron)

Data:	2023
Resum:	Tumor secreted extracellular vesicles (EVs) are potent intercellular signaling platforms. They are responsible for the accommodation of the premetastatic niche (PMN) to support cancer cell engraftment and metastatic growth. However, complex cancer cell composition within the tumor increases also the heterogeneity among cancer secreted EVs subsets, a functional diversity that has been poorly explored. This phenomenon is particularly relevant in highly plastic and heterogenous triple-negative breast cancer (TNBC), in which a significant representation of malignant cancer stem cells (CSCs) is displayed. Herein, we selectively isolated and characterized EVs from CSC or differentiated cancer cells (DCC; EVs and EVs, respectively) from the MDA-MB-231 TNBC cell line. Our results showed that EVs and EVs contain distinct bioactive cargos and therefore elicit a differential effect on stromal cells in the TME. Specifically, EVs activated secretory cancer associated fibroblasts (CAFs), triggering IL-6/IL-8 signaling and sustaining CSC phenotype maintenance. Complementarily, EVs promoted the activation of α-SMA+ myofibroblastic CAFs subpopulations and increased the endothelial remodeling, enhancing the invasive potential of TNBC cells in vitro and in vivo. In addition, solely the EVs mediated signaling prompted the transformation of healthy lungs into receptive niches able to support metastatic growth of breast cancer cells.
Ajuts:	"la Caixa" Foundation LCF/BQ/PR18/11640001 Instituto de Salud Carlos III PI20/01474 Generalitat de Catalunya 2017-SGR-638 Generalitat de Catalunya 2017-SGR-1427
Nota:	We are indebted to Unitat of Alta Tecnologia (UAT) at the Vall d'Hebron Research Institute for their assistance in flow cytometry and confocal microscopy procedures. We also thank to "Servei de Microscòpia" at the Universitat Autònoma de Barcelona (UAB) where electron microscopy analysis took place. Additionally, part of physicochemical EVs characterization and all the in vivo studies were performed by the Unique Scientific and Technical Infrastructures (ICTS) "NANBIOSIS," at the Bioengineering, Biomaterials and Nanomedicine Research Center (CIBER-BBN), specifically NTA analysis was carried out at Unit 6:Biomaterial Processing and Nanostructuring and animal experimentation at Unit 20: in vivo experimental platform (www.nanbiosis.es). We also thank Dr Pedro Fuentes and Marion Martinez for kindly providing ITGβ1 and ITGα6 antibodies, respectively.
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Publicat a:	International Journal of Cancer, Vol. 152 Núm. 10 (15 2023) , p. 2153-2165, ISSN 1097-0215

DOI: 10.1002/ijc.34447

13 p, 31.6 MB

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