Intercellular communication between extracellular vesicles from conditioned macrophages and breast cancer cells drives endocrine therapy resistance

Autores
Rodriguez Baili, María C.; Palma Cobo, Miguel; Prucca, Cesar German; Yáñez Mó, María; Gil, German Alejandro
Año de publicación
2025
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Introduction: Breast cancer is a leading cause of cancer-related mortality among women, with nearly 70% of cases being estrogen receptor-positive (ER+). While endocrine therapies, such as tamoxifen, have significantly improved patient outcomes, resistance—whether intrinsic or acquired—remains a major clinical challenge that limits treatment efficacy. Emerging evidence suggests that endocrine resistance is often driven by the presence and expansion of cancer stem cells (CSCs), which contribute to recurrence, metastasis, and therapeutic failure. The tumor microenvironment (TME), including immune cells like macrophages, soluble factors, and extracellular vesicles (EVs), plays a crucial role in promoting tumor progression and therapy resistance. EVs are small lipid bilayer-bound particles that facilitate intercellular communication by transferring bioactive cargo capable of reprogramming recipient cells.Methods: To investigate the role of macrophage-derived EVs in endocrine resistance, we isolated EVs from TNF-α-conditioned macrophages (TNF EVs) and treated MCF-7 ER+ breast cancer cells with these vesicles. We assessed changes in proliferation, migration, epithelial-mesenchymal transition (EMT), CSC-like properties, and tamoxifen resistance. Additionally, we evaluated whether tumor-derived EVs modulate macrophage polarization by analyzing the expression of PD-1 and other immunomodulatory markers.Results: TNF EV-treated MCF-7 cells showed significantly increased proliferation, enhanced migratory behavior, and morphological changes associated with EMT. Importantly, treated cells developed a stem-like phenotype, characterized by a larger CD44High/CD24Low subpopulation and improved spheroid-forming ability. These features correlated with sustained proliferation even in the presence of tamoxifen, supporting the development of endocrine resistance. Furthermore, EVs derived from tumor cells triggered macrophage polarization toward a tumor-associated macrophage (TAM) profile, with increased PD-1 expression, indicating a role in immune suppression and tumor immune evasion.Discussion: These findings emphasize the dual role of TNF-α-conditioned macrophage-derived EVs in driving both endocrine resistance and immune modulation in ER+ breast cancer. By promoting stemness, EMT, and tamoxifen resistance, as well as inducing immunosuppressive macrophage polarization, these EVs emerge as key contributors to tumor progression. Our study highlights the therapeutic potential of targeting EV-mediated communication to overcome endocrine resistance and enhance clinical outcomes for ER+ breast cancer patients. This work establishes a critical framework for future studies aimed at harnessing EVs as therapeutic targets or biomarkers in breast cancer management.
Fil: Rodriguez Baili, María C.. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; Argentina
Fil: Palma Cobo, Miguel. Universidad Autónoma de Madrid; España
Fil: Prucca, Cesar German. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; Argentina
Fil: Yáñez Mó, María. Universidad Autónoma de Madrid; España
Fil: Gil, German Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; Argentina
Materia
BREAST
CANCER
RESISTANCE
EVs
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/273690
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/273690
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Intercellular communication between extracellular vesicles from conditioned macrophages and breast cancer cells drives endocrine therapy resistanceRodriguez Baili, María C.Palma Cobo, MiguelPrucca, Cesar GermanYáñez Mó, MaríaGil, German AlejandroBREASTCANCERRESISTANCEEVshttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Introduction: Breast cancer is a leading cause of cancer-related mortality among women, with nearly 70% of cases being estrogen receptor-positive (ER+). While endocrine therapies, such as tamoxifen, have significantly improved patient outcomes, resistance—whether intrinsic or acquired—remains a major clinical challenge that limits treatment efficacy. Emerging evidence suggests that endocrine resistance is often driven by the presence and expansion of cancer stem cells (CSCs), which contribute to recurrence, metastasis, and therapeutic failure. The tumor microenvironment (TME), including immune cells like macrophages, soluble factors, and extracellular vesicles (EVs), plays a crucial role in promoting tumor progression and therapy resistance. EVs are small lipid bilayer-bound particles that facilitate intercellular communication by transferring bioactive cargo capable of reprogramming recipient cells.Methods: To investigate the role of macrophage-derived EVs in endocrine resistance, we isolated EVs from TNF-α-conditioned macrophages (TNF EVs) and treated MCF-7 ER+ breast cancer cells with these vesicles. We assessed changes in proliferation, migration, epithelial-mesenchymal transition (EMT), CSC-like properties, and tamoxifen resistance. Additionally, we evaluated whether tumor-derived EVs modulate macrophage polarization by analyzing the expression of PD-1 and other immunomodulatory markers.Results: TNF EV-treated MCF-7 cells showed significantly increased proliferation, enhanced migratory behavior, and morphological changes associated with EMT. Importantly, treated cells developed a stem-like phenotype, characterized by a larger CD44High/CD24Low subpopulation and improved spheroid-forming ability. These features correlated with sustained proliferation even in the presence of tamoxifen, supporting the development of endocrine resistance. Furthermore, EVs derived from tumor cells triggered macrophage polarization toward a tumor-associated macrophage (TAM) profile, with increased PD-1 expression, indicating a role in immune suppression and tumor immune evasion.Discussion: These findings emphasize the dual role of TNF-α-conditioned macrophage-derived EVs in driving both endocrine resistance and immune modulation in ER+ breast cancer. By promoting stemness, EMT, and tamoxifen resistance, as well as inducing immunosuppressive macrophage polarization, these EVs emerge as key contributors to tumor progression. Our study highlights the therapeutic potential of targeting EV-mediated communication to overcome endocrine resistance and enhance clinical outcomes for ER+ breast cancer patients. This work establishes a critical framework for future studies aimed at harnessing EVs as therapeutic targets or biomarkers in breast cancer management.Fil: Rodriguez Baili, María C.. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; ArgentinaFil: Palma Cobo, Miguel. Universidad Autónoma de Madrid; EspañaFil: Prucca, Cesar German. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; ArgentinaFil: Yáñez Mó, María. Universidad Autónoma de Madrid; EspañaFil: Gil, German Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; ArgentinaFrontiers Media2025-06info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/273690Rodriguez Baili, María C.; Palma Cobo, Miguel; Prucca, Cesar German; Yáñez Mó, María; Gil, German Alejandro; Intercellular communication between extracellular vesicles from conditioned macrophages and breast cancer cells drives endocrine therapy resistance; Frontiers Media; Frontiers in Cell and Developmental Biology; 13; 6-2025; 1-212296-634XCONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.frontiersin.org/articles/10.3389/fcell.2025.1548724/fullinfo:eu-repo/semantics/altIdentifier/doi/10.3389/fcell.2025.1548724info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-22T11:40:16Zoai:ri.conicet.gov.ar:11336/273690instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-10-22 11:40:16.499CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Intercellular communication between extracellular vesicles from conditioned macrophages and breast cancer cells drives endocrine therapy resistance
title Intercellular communication between extracellular vesicles from conditioned macrophages and breast cancer cells drives endocrine therapy resistance
spellingShingle Intercellular communication between extracellular vesicles from conditioned macrophages and breast cancer cells drives endocrine therapy resistance
Rodriguez Baili, María C.
BREAST
CANCER
RESISTANCE
EVs
title_short Intercellular communication between extracellular vesicles from conditioned macrophages and breast cancer cells drives endocrine therapy resistance
title_full Intercellular communication between extracellular vesicles from conditioned macrophages and breast cancer cells drives endocrine therapy resistance
title_fullStr Intercellular communication between extracellular vesicles from conditioned macrophages and breast cancer cells drives endocrine therapy resistance
title_full_unstemmed Intercellular communication between extracellular vesicles from conditioned macrophages and breast cancer cells drives endocrine therapy resistance
title_sort Intercellular communication between extracellular vesicles from conditioned macrophages and breast cancer cells drives endocrine therapy resistance
dc.creator.none.fl_str_mv Rodriguez Baili, María C.
Palma Cobo, Miguel
Prucca, Cesar German
Yáñez Mó, María
Gil, German Alejandro
author Rodriguez Baili, María C.
author_facet Rodriguez Baili, María C.
Palma Cobo, Miguel
Prucca, Cesar German
Yáñez Mó, María
Gil, German Alejandro
author_role author
author2 Palma Cobo, Miguel
Prucca, Cesar German
Yáñez Mó, María
Gil, German Alejandro
author2_role author
author
author
author
dc.subject.none.fl_str_mv BREAST
CANCER
RESISTANCE
EVs
topic BREAST
CANCER
RESISTANCE
EVs
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Introduction: Breast cancer is a leading cause of cancer-related mortality among women, with nearly 70% of cases being estrogen receptor-positive (ER+). While endocrine therapies, such as tamoxifen, have significantly improved patient outcomes, resistance—whether intrinsic or acquired—remains a major clinical challenge that limits treatment efficacy. Emerging evidence suggests that endocrine resistance is often driven by the presence and expansion of cancer stem cells (CSCs), which contribute to recurrence, metastasis, and therapeutic failure. The tumor microenvironment (TME), including immune cells like macrophages, soluble factors, and extracellular vesicles (EVs), plays a crucial role in promoting tumor progression and therapy resistance. EVs are small lipid bilayer-bound particles that facilitate intercellular communication by transferring bioactive cargo capable of reprogramming recipient cells.Methods: To investigate the role of macrophage-derived EVs in endocrine resistance, we isolated EVs from TNF-α-conditioned macrophages (TNF EVs) and treated MCF-7 ER+ breast cancer cells with these vesicles. We assessed changes in proliferation, migration, epithelial-mesenchymal transition (EMT), CSC-like properties, and tamoxifen resistance. Additionally, we evaluated whether tumor-derived EVs modulate macrophage polarization by analyzing the expression of PD-1 and other immunomodulatory markers.Results: TNF EV-treated MCF-7 cells showed significantly increased proliferation, enhanced migratory behavior, and morphological changes associated with EMT. Importantly, treated cells developed a stem-like phenotype, characterized by a larger CD44High/CD24Low subpopulation and improved spheroid-forming ability. These features correlated with sustained proliferation even in the presence of tamoxifen, supporting the development of endocrine resistance. Furthermore, EVs derived from tumor cells triggered macrophage polarization toward a tumor-associated macrophage (TAM) profile, with increased PD-1 expression, indicating a role in immune suppression and tumor immune evasion.Discussion: These findings emphasize the dual role of TNF-α-conditioned macrophage-derived EVs in driving both endocrine resistance and immune modulation in ER+ breast cancer. By promoting stemness, EMT, and tamoxifen resistance, as well as inducing immunosuppressive macrophage polarization, these EVs emerge as key contributors to tumor progression. Our study highlights the therapeutic potential of targeting EV-mediated communication to overcome endocrine resistance and enhance clinical outcomes for ER+ breast cancer patients. This work establishes a critical framework for future studies aimed at harnessing EVs as therapeutic targets or biomarkers in breast cancer management.
Fil: Rodriguez Baili, María C.. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; Argentina
Fil: Palma Cobo, Miguel. Universidad Autónoma de Madrid; España
Fil: Prucca, Cesar German. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; Argentina
Fil: Yáñez Mó, María. Universidad Autónoma de Madrid; España
Fil: Gil, German Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; Argentina
description Introduction: Breast cancer is a leading cause of cancer-related mortality among women, with nearly 70% of cases being estrogen receptor-positive (ER+). While endocrine therapies, such as tamoxifen, have significantly improved patient outcomes, resistance—whether intrinsic or acquired—remains a major clinical challenge that limits treatment efficacy. Emerging evidence suggests that endocrine resistance is often driven by the presence and expansion of cancer stem cells (CSCs), which contribute to recurrence, metastasis, and therapeutic failure. The tumor microenvironment (TME), including immune cells like macrophages, soluble factors, and extracellular vesicles (EVs), plays a crucial role in promoting tumor progression and therapy resistance. EVs are small lipid bilayer-bound particles that facilitate intercellular communication by transferring bioactive cargo capable of reprogramming recipient cells.Methods: To investigate the role of macrophage-derived EVs in endocrine resistance, we isolated EVs from TNF-α-conditioned macrophages (TNF EVs) and treated MCF-7 ER+ breast cancer cells with these vesicles. We assessed changes in proliferation, migration, epithelial-mesenchymal transition (EMT), CSC-like properties, and tamoxifen resistance. Additionally, we evaluated whether tumor-derived EVs modulate macrophage polarization by analyzing the expression of PD-1 and other immunomodulatory markers.Results: TNF EV-treated MCF-7 cells showed significantly increased proliferation, enhanced migratory behavior, and morphological changes associated with EMT. Importantly, treated cells developed a stem-like phenotype, characterized by a larger CD44High/CD24Low subpopulation and improved spheroid-forming ability. These features correlated with sustained proliferation even in the presence of tamoxifen, supporting the development of endocrine resistance. Furthermore, EVs derived from tumor cells triggered macrophage polarization toward a tumor-associated macrophage (TAM) profile, with increased PD-1 expression, indicating a role in immune suppression and tumor immune evasion.Discussion: These findings emphasize the dual role of TNF-α-conditioned macrophage-derived EVs in driving both endocrine resistance and immune modulation in ER+ breast cancer. By promoting stemness, EMT, and tamoxifen resistance, as well as inducing immunosuppressive macrophage polarization, these EVs emerge as key contributors to tumor progression. Our study highlights the therapeutic potential of targeting EV-mediated communication to overcome endocrine resistance and enhance clinical outcomes for ER+ breast cancer patients. This work establishes a critical framework for future studies aimed at harnessing EVs as therapeutic targets or biomarkers in breast cancer management.
publishDate 2025
dc.date.none.fl_str_mv 2025-06
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/273690
Rodriguez Baili, María C.; Palma Cobo, Miguel; Prucca, Cesar German; Yáñez Mó, María; Gil, German Alejandro; Intercellular communication between extracellular vesicles from conditioned macrophages and breast cancer cells drives endocrine therapy resistance; Frontiers Media; Frontiers in Cell and Developmental Biology; 13; 6-2025; 1-21
2296-634X
CONICET Digital
CONICET
url http://hdl.handle.net/11336/273690
identifier_str_mv Rodriguez Baili, María C.; Palma Cobo, Miguel; Prucca, Cesar German; Yáñez Mó, María; Gil, German Alejandro; Intercellular communication between extracellular vesicles from conditioned macrophages and breast cancer cells drives endocrine therapy resistance; Frontiers Media; Frontiers in Cell and Developmental Biology; 13; 6-2025; 1-21
2296-634X
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://www.frontiersin.org/articles/10.3389/fcell.2025.1548724/full
info:eu-repo/semantics/altIdentifier/doi/10.3389/fcell.2025.1548724
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
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eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Frontiers Media
publisher.none.fl_str_mv Frontiers Media
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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