Extracellular vesicles secreted by triple-negative breast cancer stem cells trigger premetastatic niche remodeling and metastatic growth in the lungs

Patricia González-Callejo; Petra Gener; Zamira V. Díaz-Riascos; Sefora Conti; Patricia Cámara-Sánchez; Roger Riera; Sandra Mancilla; Miguel García-Gabilondo; Vicente Peg; Diego Arango; Anna Rosell; Anna Labernadie; Xavier Trepat; Lorenzo Albertazzi; Simó Schwartz; Joaquin Seras-Franzoso; Ibane Abasolo

doi:10.1002/ijc.34447

Extracellular vesicles secreted by triple-negative breast cancer stem cells trigger premetastatic niche remodeling and metastatic growth in the lungs

Patricia González-Callejo, Petra Gener, Zamira V. Díaz-Riascos, Sefora Conti, Patricia Cámara-Sánchez, Roger Riera, Sandra Mancilla, Miguel García-Gabilondo, Vicente Peg, Diego Arango, Anna Rosell, Anna Labernadie, Xavier Trepat, Lorenzo Albertazzi, Simó Schwartz (Corresponding author), Joaquin Seras-Franzoso (Corresponding author), Ibane Abasolo

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

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^CSC and EVs^DCC, respectively) from the MDA-MB-231 TNBC cell line. Our results showed that EVs^CSC and EVs^DCC contain distinct bioactive cargos and therefore elicit a differential effect on stromal cells in the TME. Specifically, EVs^DCC activated secretory cancer associated fibroblasts (CAFs), triggering IL-6/IL-8 signaling and sustaining CSC phenotype maintenance. Complementarily, EVs^CSC 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^CSC mediated signaling prompted the transformation of healthy lungs into receptive niches able to support metastatic growth of breast cancer cells.

Original language	English
Pages (from-to)	2153-2165
Number of pages	13
Journal	International Journal of Cancer
Volume	152
Issue number	10
DOIs	https://doi.org/10.1002/ijc.34447
Publication status	Published - 15 May 2023

Bibliographical note

Funding Information:
Our study was supported by ISCIII PI20/01474 (co‐founded by Fondo Europeo de Desarrollo Regional [FEDER]) granted to Simó Schwartz Jr and Petra Gener, the 2017‐SGR‐638 and ‐1427 form the Generalitat de Catalunya to Simó Schwartz Jr and Anna Rose, respectively, and PENTRI‐2 from CIBER‐BBN granted to Ibane Abasolo. Anna Labernadie is recipient of Obra Social “La Caixa” Junior Leader Postdoctoral Fellowship, (LCF/BQ/PR18/11640001). Joaquin Seras‐Franzoso was awarded with an Asociación Española Contra el Cancer (AECC), (AIO14142112SERA) post‐doctoral fellowship.

Funding

Our study was supported by ISCIII PI20/01474 (co‐founded by Fondo Europeo de Desarrollo Regional [FEDER]) granted to Simó Schwartz Jr and Petra Gener, the 2017‐SGR‐638 and ‐1427 form the Generalitat de Catalunya to Simó Schwartz Jr and Anna Rose, respectively, and PENTRI‐2 from CIBER‐BBN granted to Ibane Abasolo. Anna Labernadie is recipient of Obra Social “La Caixa” Junior Leader Postdoctoral Fellowship, (LCF/BQ/PR18/11640001). Joaquin Seras‐Franzoso was awarded with an Asociación Española Contra el Cancer (AECC), (AIO14142112SERA) post‐doctoral fellowship.

Funders	Funder number
International Centre for Theoretical Sciences
Generalitat de Catalunya	PENTRI‐2, LCF/BQ/PR18/11640001
Federación Española de Enfermedades Raras
Instituto de Salud Carlos III	PI20/01474
European Regional Development Fund

Keywords

cancer cell plasticity
extracellular vesicles
premetastatic niche
triple-negative breast cancer
tumor microenvironment

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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González-Callejo, P., Gener, P., Díaz-Riascos, Z. V., Conti, S., Cámara-Sánchez, P., Riera, R., Mancilla, S., García-Gabilondo, M., Peg, V., Arango, D., Rosell, A., Labernadie, A., Trepat, X., Albertazzi, L., Schwartz, S., Seras-Franzoso, J., & Abasolo, I. (2023). Extracellular vesicles secreted by triple-negative breast cancer stem cells trigger premetastatic niche remodeling and metastatic growth in the lungs. International Journal of Cancer, 152(10), 2153-2165. https://doi.org/10.1002/ijc.34447

@article{1d24771faef04a9a888ad4ac0bc93b53,

title = "Extracellular vesicles secreted by triple-negative breast cancer stem cells trigger premetastatic niche remodeling and metastatic growth in the lungs",

abstract = "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; EVsCSC and EVsDCC, respectively) from the MDA-MB-231 TNBC cell line. Our results showed that EVsCSC and EVsDCC contain distinct bioactive cargos and therefore elicit a differential effect on stromal cells in the TME. Specifically, EVsDCC activated secretory cancer associated fibroblasts (CAFs), triggering IL-6/IL-8 signaling and sustaining CSC phenotype maintenance. Complementarily, EVsCSC 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 EVsCSC mediated signaling prompted the transformation of healthy lungs into receptive niches able to support metastatic growth of breast cancer cells.",

keywords = "cancer cell plasticity, extracellular vesicles, premetastatic niche, triple-negative breast cancer, tumor microenvironment",

author = "Patricia Gonz{\'a}lez-Callejo and Petra Gener and D{\'i}az-Riascos, \{Zamira V.\} and Sefora Conti and Patricia C{\'a}mara-S{\'a}nchez and Roger Riera and Sandra Mancilla and Miguel Garc{\'i}a-Gabilondo and Vicente Peg and Diego Arango and Anna Rosell and Anna Labernadie and Xavier Trepat and Lorenzo Albertazzi and Sim{\'o} Schwartz and Joaquin Seras-Franzoso and Ibane Abasolo",

note = "Funding Information: Our study was supported by ISCIII PI20/01474 (co‐founded by Fondo Europeo de Desarrollo Regional [FEDER]) granted to Sim{\'o} Schwartz Jr and Petra Gener, the 2017‐SGR‐638 and ‐1427 form the Generalitat de Catalunya to Sim{\'o} Schwartz Jr and Anna Rose, respectively, and PENTRI‐2 from CIBER‐BBN granted to Ibane Abasolo. Anna Labernadie is recipient of Obra Social “La Caixa” Junior Leader Postdoctoral Fellowship, (LCF/BQ/PR18/11640001). Joaquin Seras‐Franzoso was awarded with an Asociaci{\'o}n Espa{\~n}ola Contra el Cancer (AECC), (AIO14142112SERA) post‐doctoral fellowship. ",

year = "2023",

month = may,

day = "15",

doi = "10.1002/ijc.34447",

language = "English",

volume = "152",

pages = "2153--2165",

journal = "International Journal of Cancer",

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González-Callejo, P, Gener, P, Díaz-Riascos, ZV, Conti, S, Cámara-Sánchez, P, Riera, R, Mancilla, S, García-Gabilondo, M, Peg, V, Arango, D, Rosell, A, Labernadie, A, Trepat, X, Albertazzi, L, Schwartz, S, Seras-Franzoso, J & Abasolo, I 2023, 'Extracellular vesicles secreted by triple-negative breast cancer stem cells trigger premetastatic niche remodeling and metastatic growth in the lungs', International Journal of Cancer, vol. 152, no. 10, pp. 2153-2165. https://doi.org/10.1002/ijc.34447

Extracellular vesicles secreted by triple-negative breast cancer stem cells trigger premetastatic niche remodeling and metastatic growth in the lungs. / González-Callejo, Patricia; Gener, Petra; Díaz-Riascos, Zamira V. et al.
In: International Journal of Cancer, Vol. 152, No. 10, 15.05.2023, p. 2153-2165.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - Extracellular vesicles secreted by triple-negative breast cancer stem cells trigger premetastatic niche remodeling and metastatic growth in the lungs

AU - González-Callejo, Patricia

AU - Gener, Petra

AU - Díaz-Riascos, Zamira V.

AU - Conti, Sefora

AU - Cámara-Sánchez, Patricia

AU - Riera, Roger

AU - Mancilla, Sandra

AU - García-Gabilondo, Miguel

AU - Peg, Vicente

AU - Arango, Diego

AU - Rosell, Anna

AU - Labernadie, Anna

AU - Trepat, Xavier

AU - Albertazzi, Lorenzo

AU - Schwartz, Simó

AU - Seras-Franzoso, Joaquin

AU - Abasolo, Ibane

N1 - Funding Information: Our study was supported by ISCIII PI20/01474 (co‐founded by Fondo Europeo de Desarrollo Regional [FEDER]) granted to Simó Schwartz Jr and Petra Gener, the 2017‐SGR‐638 and ‐1427 form the Generalitat de Catalunya to Simó Schwartz Jr and Anna Rose, respectively, and PENTRI‐2 from CIBER‐BBN granted to Ibane Abasolo. Anna Labernadie is recipient of Obra Social “La Caixa” Junior Leader Postdoctoral Fellowship, (LCF/BQ/PR18/11640001). Joaquin Seras‐Franzoso was awarded with an Asociación Española Contra el Cancer (AECC), (AIO14142112SERA) post‐doctoral fellowship.

PY - 2023/5/15

Y1 - 2023/5/15

N2 - 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; EVsCSC and EVsDCC, respectively) from the MDA-MB-231 TNBC cell line. Our results showed that EVsCSC and EVsDCC contain distinct bioactive cargos and therefore elicit a differential effect on stromal cells in the TME. Specifically, EVsDCC activated secretory cancer associated fibroblasts (CAFs), triggering IL-6/IL-8 signaling and sustaining CSC phenotype maintenance. Complementarily, EVsCSC 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 EVsCSC mediated signaling prompted the transformation of healthy lungs into receptive niches able to support metastatic growth of breast cancer cells.

AB - 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; EVsCSC and EVsDCC, respectively) from the MDA-MB-231 TNBC cell line. Our results showed that EVsCSC and EVsDCC contain distinct bioactive cargos and therefore elicit a differential effect on stromal cells in the TME. Specifically, EVsDCC activated secretory cancer associated fibroblasts (CAFs), triggering IL-6/IL-8 signaling and sustaining CSC phenotype maintenance. Complementarily, EVsCSC 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 EVsCSC mediated signaling prompted the transformation of healthy lungs into receptive niches able to support metastatic growth of breast cancer cells.

KW - cancer cell plasticity

KW - extracellular vesicles

KW - premetastatic niche

KW - triple-negative breast cancer

KW - tumor microenvironment

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DO - 10.1002/ijc.34447

M3 - Article

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AN - SCOPUS:85147518428

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JO - International Journal of Cancer

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IS - 10

ER -

Extracellular vesicles secreted by triple-negative breast cancer stem cells trigger premetastatic niche remodeling and metastatic growth in the lungs

Abstract

Bibliographical note

Funding

Keywords

UN SDGs

Access to Document

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