Autophagy protects from trastuzumabInduced cytotoxicity in HER2 overexpressing breast tumor spheroids

Autores
Rodríguez, C. E.; Reidel, S. I.; Bal de Kier Joffé, E. D.; Jasnis, M. A.; Fiszman, G. L.
Año de publicación
2015
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Multicellular tumor spheroids represent a 3D in vitro model that mimics solid tumor essential properties including assembly and development of extracellular matrix and nutrient, oxygen and proliferation gradients. In the present study, we analyze the impact of 3D spatial organization of HER2-overexpressing breast cancer cells on the response to Trastuzumab. We cultured human mammary adenocarcinoma cell lines as spheroids with the hanging drop method and we observed a gradient of proliferating, quiescent, hypoxic, apoptotic and autophagic cells towards the inner core. This 3D organization decreased Trastuzumab sensitivity of HER2 over-expressing cells compared to monolayer cell cultures. We did not observe apoptosis induced by Trastuzumab but found cell arrest in G0/G1 phase. Moreover, the treatment downregulated the basal apoptosis only found in tumor spheroids, by eliciting protective autophagy. We were able to increase sensitivity to Trastuzumab by autophagy inhibition, thus exposing the interaction between apoptosis and autophagy. We confirmed this result by developing a resistant cell line that was more sensitive to autophagy inhibition than the parental BT474 cells. In summary, the development of Trastuzumab resistance relies on the balance between death and survival mechanisms, characteristic of 3D cell organization. We propose the use of spheroids to further improve the understanding of Trastuzumab antitumor activity and overcome resistance.
Fil: Rodríguez, C. E. Universidad de Buenos Aires. Instituto de Oncología Ángel H. Roffo; Argentina
Fil: Reidel, S. I. Instituto Nacional de Tecnología Industrial. INTI-Biotecnología Industrial; Argentina
Fil: Bal de Kier Joffé, E. D. Universidad de Buenos Aires. Instituto de Oncología Ángel H. Roffo; Argentina
Fil: Jasnis, M. A. Universidad de Buenos Aires. Instituto de Oncología Ángel H. Roffo; Argentina
Fil: Fiszman, G. L. Instituto Nacional de Tecnología Industrial. INTI-Biotecnología Industrial; Argentina
Fuente
PLoS ONE, 10(9)
Materia
Cáncer
Células
Medicina
Quimioterapia
Citología
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by/4.0/
Repositorio
Repositorio Institucional del Instituto Nacional de Tecnología Industrial (INTI)
Institución
Instituto Nacional de Tecnología Industrial
OAI Identificador
nuevadc:Reidel2015Autophagy_pdf
Acceder
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oai_identifier_str nuevadc:Reidel2015Autophagy_pdf
network_acronym_str RIINTI
repository_id_str
network_name_str Repositorio Institucional del Instituto Nacional de Tecnología Industrial (INTI)
spelling Autophagy protects from trastuzumabInduced cytotoxicity in HER2 overexpressing breast tumor spheroidsRodríguez, C. E.Reidel, S. I.Bal de Kier Joffé, E. D.Jasnis, M. A.Fiszman, G. L.CáncerCélulasMedicinaQuimioterapiaCitologíaMulticellular tumor spheroids represent a 3D in vitro model that mimics solid tumor essential properties including assembly and development of extracellular matrix and nutrient, oxygen and proliferation gradients. In the present study, we analyze the impact of 3D spatial organization of HER2-overexpressing breast cancer cells on the response to Trastuzumab. We cultured human mammary adenocarcinoma cell lines as spheroids with the hanging drop method and we observed a gradient of proliferating, quiescent, hypoxic, apoptotic and autophagic cells towards the inner core. This 3D organization decreased Trastuzumab sensitivity of HER2 over-expressing cells compared to monolayer cell cultures. We did not observe apoptosis induced by Trastuzumab but found cell arrest in G0/G1 phase. Moreover, the treatment downregulated the basal apoptosis only found in tumor spheroids, by eliciting protective autophagy. We were able to increase sensitivity to Trastuzumab by autophagy inhibition, thus exposing the interaction between apoptosis and autophagy. We confirmed this result by developing a resistant cell line that was more sensitive to autophagy inhibition than the parental BT474 cells. In summary, the development of Trastuzumab resistance relies on the balance between death and survival mechanisms, characteristic of 3D cell organization. We propose the use of spheroids to further improve the understanding of Trastuzumab antitumor activity and overcome resistance.Fil: Rodríguez, C. E. Universidad de Buenos Aires. Instituto de Oncología Ángel H. Roffo; ArgentinaFil: Reidel, S. I. Instituto Nacional de Tecnología Industrial. INTI-Biotecnología Industrial; ArgentinaFil: Bal de Kier Joffé, E. D. Universidad de Buenos Aires. Instituto de Oncología Ángel H. Roffo; ArgentinaFil: Jasnis, M. A. Universidad de Buenos Aires. Instituto de Oncología Ángel H. Roffo; ArgentinaFil: Fiszman, G. L. Instituto Nacional de Tecnología Industrial. INTI-Biotecnología Industrial; ArgentinaPLOS2015info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfReidel2015Autophagy.pdfhttps://app.inti.gob.ar/greenstone3/sites/localsite/collect/nuevadc/index/assoc/Reidel20.dir/doc.pdfPLoS ONE, 10(9)reponame:Repositorio Institucional del Instituto Nacional de Tecnología Industrial (INTI)instname:Instituto Nacional de Tecnología Industrialenginfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/4.0/openAccess2026-03-26T12:48:50Znuevadc:Reidel2015Autophagy_pdfinstacron:INTIInstitucionalhttps://app.inti.gob.ar/greenstone3/biblioOrganismo científico-tecnológicohttps://argentina.gob.ar/intihttps://app.inti.gob.ar/greenstone3/oaiserver?verb=Identifypfalcato@inti.gob.arArgentinaopendoar:2026-03-26 12:48:50.753Repositorio Institucional del Instituto Nacional de Tecnología Industrial (INTI) - Instituto Nacional de Tecnología Industrialfalse
dc.title.none.fl_str_mv Autophagy protects from trastuzumabInduced cytotoxicity in HER2 overexpressing breast tumor spheroids
title Autophagy protects from trastuzumabInduced cytotoxicity in HER2 overexpressing breast tumor spheroids
spellingShingle Autophagy protects from trastuzumabInduced cytotoxicity in HER2 overexpressing breast tumor spheroids
Rodríguez, C. E.
Cáncer
Células
Medicina
Quimioterapia
Citología
title_short Autophagy protects from trastuzumabInduced cytotoxicity in HER2 overexpressing breast tumor spheroids
title_full Autophagy protects from trastuzumabInduced cytotoxicity in HER2 overexpressing breast tumor spheroids
title_fullStr Autophagy protects from trastuzumabInduced cytotoxicity in HER2 overexpressing breast tumor spheroids
title_full_unstemmed Autophagy protects from trastuzumabInduced cytotoxicity in HER2 overexpressing breast tumor spheroids
title_sort Autophagy protects from trastuzumabInduced cytotoxicity in HER2 overexpressing breast tumor spheroids
dc.creator.none.fl_str_mv Rodríguez, C. E.
Reidel, S. I.
Bal de Kier Joffé, E. D.
Jasnis, M. A.
Fiszman, G. L.
author Rodríguez, C. E.
author_facet Rodríguez, C. E.
Reidel, S. I.
Bal de Kier Joffé, E. D.
Jasnis, M. A.
Fiszman, G. L.
author_role author
author2 Reidel, S. I.
Bal de Kier Joffé, E. D.
Jasnis, M. A.
Fiszman, G. L.
author2_role author
author
author
author
dc.subject.none.fl_str_mv Cáncer
Células
Medicina
Quimioterapia
Citología
topic Cáncer
Células
Medicina
Quimioterapia
Citología
dc.description.none.fl_txt_mv Multicellular tumor spheroids represent a 3D in vitro model that mimics solid tumor essential properties including assembly and development of extracellular matrix and nutrient, oxygen and proliferation gradients. In the present study, we analyze the impact of 3D spatial organization of HER2-overexpressing breast cancer cells on the response to Trastuzumab. We cultured human mammary adenocarcinoma cell lines as spheroids with the hanging drop method and we observed a gradient of proliferating, quiescent, hypoxic, apoptotic and autophagic cells towards the inner core. This 3D organization decreased Trastuzumab sensitivity of HER2 over-expressing cells compared to monolayer cell cultures. We did not observe apoptosis induced by Trastuzumab but found cell arrest in G0/G1 phase. Moreover, the treatment downregulated the basal apoptosis only found in tumor spheroids, by eliciting protective autophagy. We were able to increase sensitivity to Trastuzumab by autophagy inhibition, thus exposing the interaction between apoptosis and autophagy. We confirmed this result by developing a resistant cell line that was more sensitive to autophagy inhibition than the parental BT474 cells. In summary, the development of Trastuzumab resistance relies on the balance between death and survival mechanisms, characteristic of 3D cell organization. We propose the use of spheroids to further improve the understanding of Trastuzumab antitumor activity and overcome resistance.
Fil: Rodríguez, C. E. Universidad de Buenos Aires. Instituto de Oncología Ángel H. Roffo; Argentina
Fil: Reidel, S. I. Instituto Nacional de Tecnología Industrial. INTI-Biotecnología Industrial; Argentina
Fil: Bal de Kier Joffé, E. D. Universidad de Buenos Aires. Instituto de Oncología Ángel H. Roffo; Argentina
Fil: Jasnis, M. A. Universidad de Buenos Aires. Instituto de Oncología Ángel H. Roffo; Argentina
Fil: Fiszman, G. L. Instituto Nacional de Tecnología Industrial. INTI-Biotecnología Industrial; Argentina
description Multicellular tumor spheroids represent a 3D in vitro model that mimics solid tumor essential properties including assembly and development of extracellular matrix and nutrient, oxygen and proliferation gradients. In the present study, we analyze the impact of 3D spatial organization of HER2-overexpressing breast cancer cells on the response to Trastuzumab. We cultured human mammary adenocarcinoma cell lines as spheroids with the hanging drop method and we observed a gradient of proliferating, quiescent, hypoxic, apoptotic and autophagic cells towards the inner core. This 3D organization decreased Trastuzumab sensitivity of HER2 over-expressing cells compared to monolayer cell cultures. We did not observe apoptosis induced by Trastuzumab but found cell arrest in G0/G1 phase. Moreover, the treatment downregulated the basal apoptosis only found in tumor spheroids, by eliciting protective autophagy. We were able to increase sensitivity to Trastuzumab by autophagy inhibition, thus exposing the interaction between apoptosis and autophagy. We confirmed this result by developing a resistant cell line that was more sensitive to autophagy inhibition than the parental BT474 cells. In summary, the development of Trastuzumab resistance relies on the balance between death and survival mechanisms, characteristic of 3D cell organization. We propose the use of spheroids to further improve the understanding of Trastuzumab antitumor activity and overcome resistance.
publishDate 2015
dc.date.none.fl_str_mv 2015
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 Reidel2015Autophagy.pdf
https://app.inti.gob.ar/greenstone3/sites/localsite/collect/nuevadc/index/assoc/Reidel20.dir/doc.pdf
identifier_str_mv Reidel2015Autophagy.pdf
url https://app.inti.gob.ar/greenstone3/sites/localsite/collect/nuevadc/index/assoc/Reidel20.dir/doc.pdf
dc.language.none.fl_str_mv eng
language eng
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by/4.0/
openAccess
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by/4.0/
openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv PLOS
publisher.none.fl_str_mv PLOS
dc.source.none.fl_str_mv PLoS ONE, 10(9)
reponame:Repositorio Institucional del Instituto Nacional de Tecnología Industrial (INTI)
instname:Instituto Nacional de Tecnología Industrial
reponame_str Repositorio Institucional del Instituto Nacional de Tecnología Industrial (INTI)
collection Repositorio Institucional del Instituto Nacional de Tecnología Industrial (INTI)
instname_str Instituto Nacional de Tecnología Industrial
repository.name.fl_str_mv Repositorio Institucional del Instituto Nacional de Tecnología Industrial (INTI) - Instituto Nacional de Tecnología Industrial
repository.mail.fl_str_mv pfalcato@inti.gob.ar
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score 13.231807

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