Abrogation of stemness in osteosarcoma by the mithramycin analog EC-8042 is mediated by its ability to inhibit NOTCH-1 signaling

Osteosarcomas are frequently associated to a poor prognosis and a modest response to current treatments. EC-8042 is a well-tolerated mithramycin analog that has demonstrated an efficient ability to eliminate tumor cells, including cancer stem cell subpopulations (CSC), in sarcomas. In transcriptomic...

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Autores: Estupiñán, Óscar, Rey, Verónica, Tornín, Juan, Murillo, Dzohara, Gallego, Borja, Huergo, Carmen, Blanco Lorenzo, Verónica, González Meana, M. Victoria, Rodríguez Pérez, Aida, Moris, Francisco, González Miranda, Jessica, Ayllón, Verónica, Ramos-Mejía, Verónica, Bigas Salvans, Anna, Rodríguez, René
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2023
País:España
Institución:Universitat Pompeu Fabra
Repositorio:Repositorio Digital de la UPF
OAI Identifier:oai:repositori.upf.edu:10230/59215
Acceso en línea:http://hdl.handle.net/10230/59215
http://dx.doi.org/10.1016/j.biopha.2023.114627
Access Level:acceso abierto
Palabra clave:Cancer stem cells
EC-8042
HES1
Mithramycin
NOTCH1
Osteosarcoma
Sarcoma
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spelling Abrogation of stemness in osteosarcoma by the mithramycin analog EC-8042 is mediated by its ability to inhibit NOTCH-1 signalingEstupiñán, ÓscarRey, VerónicaTornín, JuanMurillo, DzoharaGallego, BorjaHuergo, CarmenBlanco Lorenzo, VerónicaGonzález Meana, M. VictoriaRodríguez Pérez, AidaMoris, FranciscoGonzález Miranda, JessicaAyllón, VerónicaRamos-Mejía, VerónicaBigas Salvans, AnnaRodríguez, RenéCancer stem cellsEC-8042HES1MithramycinNOTCH1OsteosarcomaSarcomaOsteosarcomas are frequently associated to a poor prognosis and a modest response to current treatments. EC-8042 is a well-tolerated mithramycin analog that has demonstrated an efficient ability to eliminate tumor cells, including cancer stem cell subpopulations (CSC), in sarcomas. In transcriptomic and protein expression analyses, we identified NOTCH1 signaling as one of the main pro-stemness pathways repressed by EC-8042 in osteosarcomas. Overexpression of NOTCH-1 resulted in a reduced anti-tumor effect of EC-8042 in CSC-enriched 3D tumorspheres cultures. On the other hand, the depletion of the NOTCH-1 downstream target HES-1 was able to enhance the action of EC-8042 on CSCs. Moreover, HES1 depleted cells failed to recover after treatment withdrawal and showed reduced tumor growth potential in vivo. In contrast, mice xenografted with NOTCH1-overexpressing cells responded worse than parental cells to EC-8042. Finally, we found that active NOTCH1 levels in sarcoma patients was associated to advanced disease and lower survival. Overall, these data highlight the relevant role that NOTCH1 signaling plays in mediating stemness in osteosarcoma. Moreover, we demonstrate that EC-8042 is powerful inhibitor of NOTCH signaling and that the anti-CSC activity of this mithramycin analog highly rely on its ability to repress this pathway.This work was supported by the Agencia Estatal de Investigación (AEI) [MICINN/Fondo Europeo de Desarrollo Regional (FEDER) (grant PID2019–106666RB-I00 to R.R.) and ISC III/FEDER (Consorcio CIBERONC - CB16/12/00390)] and the Plan de Ciencia Tecnología e Innovación del Principado de Asturias/FEDER [grant IDI/2021/000027 and Severo Ochoa predoctoral fellowships BP-17–108 to O.E., BP‐ 20–046 to B.G. and BP-21–084 to DM].Elsevier202420242023info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttp://hdl.handle.net/10230/59215http://dx.doi.org/10.1016/j.biopha.2023.114627reponame:Repositorio Digital de la UPFinstname:Universitat Pompeu FabraInglésBiomed Pharmacother. 2023 Jun;162:114627info:eu-repo/grantAgreement/ES/2PE/PID2019–106666RB-I00© 2023 The Authors. Published by Elsevier Masson SAS. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).http://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:repositori.upf.edu:10230/592152026-06-12T07:21:37Z
dc.title.none.fl_str_mv Abrogation of stemness in osteosarcoma by the mithramycin analog EC-8042 is mediated by its ability to inhibit NOTCH-1 signaling
title Abrogation of stemness in osteosarcoma by the mithramycin analog EC-8042 is mediated by its ability to inhibit NOTCH-1 signaling
spellingShingle Abrogation of stemness in osteosarcoma by the mithramycin analog EC-8042 is mediated by its ability to inhibit NOTCH-1 signaling
Estupiñán, Óscar
Cancer stem cells
EC-8042
HES1
Mithramycin
NOTCH1
Osteosarcoma
Sarcoma
title_short Abrogation of stemness in osteosarcoma by the mithramycin analog EC-8042 is mediated by its ability to inhibit NOTCH-1 signaling
title_full Abrogation of stemness in osteosarcoma by the mithramycin analog EC-8042 is mediated by its ability to inhibit NOTCH-1 signaling
title_fullStr Abrogation of stemness in osteosarcoma by the mithramycin analog EC-8042 is mediated by its ability to inhibit NOTCH-1 signaling
title_full_unstemmed Abrogation of stemness in osteosarcoma by the mithramycin analog EC-8042 is mediated by its ability to inhibit NOTCH-1 signaling
title_sort Abrogation of stemness in osteosarcoma by the mithramycin analog EC-8042 is mediated by its ability to inhibit NOTCH-1 signaling
dc.creator.none.fl_str_mv Estupiñán, Óscar
Rey, Verónica
Tornín, Juan
Murillo, Dzohara
Gallego, Borja
Huergo, Carmen
Blanco Lorenzo, Verónica
González Meana, M. Victoria
Rodríguez Pérez, Aida
Moris, Francisco
González Miranda, Jessica
Ayllón, Verónica
Ramos-Mejía, Verónica
Bigas Salvans, Anna
Rodríguez, René
author Estupiñán, Óscar
author_facet Estupiñán, Óscar
Rey, Verónica
Tornín, Juan
Murillo, Dzohara
Gallego, Borja
Huergo, Carmen
Blanco Lorenzo, Verónica
González Meana, M. Victoria
Rodríguez Pérez, Aida
Moris, Francisco
González Miranda, Jessica
Ayllón, Verónica
Ramos-Mejía, Verónica
Bigas Salvans, Anna
Rodríguez, René
author_role author
author2 Rey, Verónica
Tornín, Juan
Murillo, Dzohara
Gallego, Borja
Huergo, Carmen
Blanco Lorenzo, Verónica
González Meana, M. Victoria
Rodríguez Pérez, Aida
Moris, Francisco
González Miranda, Jessica
Ayllón, Verónica
Ramos-Mejía, Verónica
Bigas Salvans, Anna
Rodríguez, René
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Cancer stem cells
EC-8042
HES1
Mithramycin
NOTCH1
Osteosarcoma
Sarcoma
topic Cancer stem cells
EC-8042
HES1
Mithramycin
NOTCH1
Osteosarcoma
Sarcoma
description Osteosarcomas are frequently associated to a poor prognosis and a modest response to current treatments. EC-8042 is a well-tolerated mithramycin analog that has demonstrated an efficient ability to eliminate tumor cells, including cancer stem cell subpopulations (CSC), in sarcomas. In transcriptomic and protein expression analyses, we identified NOTCH1 signaling as one of the main pro-stemness pathways repressed by EC-8042 in osteosarcomas. Overexpression of NOTCH-1 resulted in a reduced anti-tumor effect of EC-8042 in CSC-enriched 3D tumorspheres cultures. On the other hand, the depletion of the NOTCH-1 downstream target HES-1 was able to enhance the action of EC-8042 on CSCs. Moreover, HES1 depleted cells failed to recover after treatment withdrawal and showed reduced tumor growth potential in vivo. In contrast, mice xenografted with NOTCH1-overexpressing cells responded worse than parental cells to EC-8042. Finally, we found that active NOTCH1 levels in sarcoma patients was associated to advanced disease and lower survival. Overall, these data highlight the relevant role that NOTCH1 signaling plays in mediating stemness in osteosarcoma. Moreover, we demonstrate that EC-8042 is powerful inhibitor of NOTCH signaling and that the anti-CSC activity of this mithramycin analog highly rely on its ability to repress this pathway.
publishDate 2023
dc.date.none.fl_str_mv 2023
2024
2024
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10230/59215
http://dx.doi.org/10.1016/j.biopha.2023.114627
url http://hdl.handle.net/10230/59215
http://dx.doi.org/10.1016/j.biopha.2023.114627
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Biomed Pharmacother. 2023 Jun;162:114627
info:eu-repo/grantAgreement/ES/2PE/PID2019–106666RB-I00
dc.rights.none.fl_str_mv http://creativecommons.org/licenses/by/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv reponame:Repositorio Digital de la UPF
instname:Universitat Pompeu Fabra
instname_str Universitat Pompeu Fabra
reponame_str Repositorio Digital de la UPF
collection Repositorio Digital de la UPF
repository.name.fl_str_mv
repository.mail.fl_str_mv
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