Tetralol derivative NNC-55-0396 targets hypoxic cells in the glioblastoma microenvironment: an organ-on-chip approach

Glioblastoma (GBM) is a highly malignant brain tumour characterised by limited treatment options and poor prognosis. The tumour microenvironment, particularly the central hypoxic region of the tumour, is known to play a pivotal role in GBM progression. Cells within this region adapt to hypoxia by st...

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Autores: Bayona, Clara, Alza, Lía, Ranđelović, Teodora, Sallán, Marta C., Visa Pretel, Anna, Cantí Nicolás, Carles, Ochoa, Ignacio, Oliván, Sara, Herreros Danés, Judit
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2024
País:España
Recursos:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:10459.1/465078
Acesso em linha:https://doi.org/10.1038/s41419-024-06492-1
https://hdl.handle.net/10459.1/465078
Access Level:acceso abierto
Palavra-chave:Cancer microenvironment
Cancer models
Microfluidics
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spelling Tetralol derivative NNC-55-0396 targets hypoxic cells in the glioblastoma microenvironment: an organ-on-chip approachBayona, ClaraAlza, LíaRanđelović, TeodoraSallán, Marta C.Visa Pretel, AnnaCantí Nicolás, CarlesOchoa, IgnacioOliván, SaraHerreros Danés, JuditCancer microenvironmentCancer modelsMicrofluidicsGlioblastoma (GBM) is a highly malignant brain tumour characterised by limited treatment options and poor prognosis. The tumour microenvironment, particularly the central hypoxic region of the tumour, is known to play a pivotal role in GBM progression. Cells within this region adapt to hypoxia by stabilising transcription factor HIF1-α, which promotes cell proliferation, dedifferentiation and chemoresistance. In this study we sought to examine the effects of NNC-55-0396, a tetralol compound which overactivates the unfolded protein response inducing apoptosis, using the organ-on-chip technology. We identified an increased sensitivity of the hypoxic core of the chip to NNC, which correlates with decreasing levels of HIF1-α in vitro. Moreover, NNC blocks the macroautophagic process that is unleashed by hypoxia as revealed by increased levels of autophagosomal constituent LC3-II and autophagy chaperone p62/SQSTM1. The specific effects of NNC in the hypoxic microenvironment unveil additional anti-cancer abilities of this compound and further support investigations on its use in combined therapies against GBM.This work was supported by the European Union’s Horizon 2020 research and innovation programme under grant agreement No 829010 (PRIME H2020-FETOPEN-2018-2019-2020-01). We also acknowledge the financial support from the Spanish Ministry of Economy and Competitiveness (MINECO fellowship, DIN 2020-011544); Ministry of Science and Innovation, the European Regional Development Fund (Proyect PID2021-126051OB-C41 funded by MCIN/AEI/10.13039/501100011033/FEDER, UE); MINECO Retos Program RTI2018-094739-B-I00 to CC and JH) and Fundació La Marató de TV3 (201909-30 to CC). CB would like to thank the Government of Aragon (DGA) for the predoctoral funding. AV is funded by Asociación Española Contra el Cáncer and LA is a recipient of an FI-AGAUR fellowship. We are grateful to Maria Casals and David Argilés for technical assistance. Cell culture experiments were performed in the Cell Culture Technical Scientific Service, Universitat de Lleida (Lleida, Catalonia, Spain). Authors would like to acknowledge the use of Servicio General de Apoyo a la Investigación-SAI, Universidad de Zaragoza.Springer Nature2024info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://doi.org/10.1038/s41419-024-06492-1https://hdl.handle.net/10459.1/465078reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)Inglésinfo:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/RTI2018-094739-B-I00Reproducció del document publicat a: https://doi.org/10.1038/s41419-024-06492-1Cell Death & Disease, 2024, vol. 15, num. 127info:eu-repo/grantAgreement/EC/H2020/829010cc-by (c) Authors, 2024info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-sa/4.0oai:recercat.cat:10459.1/4650782026-05-29T05:05:01Z
dc.title.none.fl_str_mv Tetralol derivative NNC-55-0396 targets hypoxic cells in the glioblastoma microenvironment: an organ-on-chip approach
title Tetralol derivative NNC-55-0396 targets hypoxic cells in the glioblastoma microenvironment: an organ-on-chip approach
spellingShingle Tetralol derivative NNC-55-0396 targets hypoxic cells in the glioblastoma microenvironment: an organ-on-chip approach
Bayona, Clara
Cancer microenvironment
Cancer models
Microfluidics
title_short Tetralol derivative NNC-55-0396 targets hypoxic cells in the glioblastoma microenvironment: an organ-on-chip approach
title_full Tetralol derivative NNC-55-0396 targets hypoxic cells in the glioblastoma microenvironment: an organ-on-chip approach
title_fullStr Tetralol derivative NNC-55-0396 targets hypoxic cells in the glioblastoma microenvironment: an organ-on-chip approach
title_full_unstemmed Tetralol derivative NNC-55-0396 targets hypoxic cells in the glioblastoma microenvironment: an organ-on-chip approach
title_sort Tetralol derivative NNC-55-0396 targets hypoxic cells in the glioblastoma microenvironment: an organ-on-chip approach
dc.creator.none.fl_str_mv Bayona, Clara
Alza, Lía
Ranđelović, Teodora
Sallán, Marta C.
Visa Pretel, Anna
Cantí Nicolás, Carles
Ochoa, Ignacio
Oliván, Sara
Herreros Danés, Judit
author Bayona, Clara
author_facet Bayona, Clara
Alza, Lía
Ranđelović, Teodora
Sallán, Marta C.
Visa Pretel, Anna
Cantí Nicolás, Carles
Ochoa, Ignacio
Oliván, Sara
Herreros Danés, Judit
author_role author
author2 Alza, Lía
Ranđelović, Teodora
Sallán, Marta C.
Visa Pretel, Anna
Cantí Nicolás, Carles
Ochoa, Ignacio
Oliván, Sara
Herreros Danés, Judit
author2_role author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Cancer microenvironment
Cancer models
Microfluidics
topic Cancer microenvironment
Cancer models
Microfluidics
description Glioblastoma (GBM) is a highly malignant brain tumour characterised by limited treatment options and poor prognosis. The tumour microenvironment, particularly the central hypoxic region of the tumour, is known to play a pivotal role in GBM progression. Cells within this region adapt to hypoxia by stabilising transcription factor HIF1-α, which promotes cell proliferation, dedifferentiation and chemoresistance. In this study we sought to examine the effects of NNC-55-0396, a tetralol compound which overactivates the unfolded protein response inducing apoptosis, using the organ-on-chip technology. We identified an increased sensitivity of the hypoxic core of the chip to NNC, which correlates with decreasing levels of HIF1-α in vitro. Moreover, NNC blocks the macroautophagic process that is unleashed by hypoxia as revealed by increased levels of autophagosomal constituent LC3-II and autophagy chaperone p62/SQSTM1. The specific effects of NNC in the hypoxic microenvironment unveil additional anti-cancer abilities of this compound and further support investigations on its use in combined therapies against GBM.
publishDate 2024
dc.date.none.fl_str_mv 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 https://doi.org/10.1038/s41419-024-06492-1
https://hdl.handle.net/10459.1/465078
url https://doi.org/10.1038/s41419-024-06492-1
https://hdl.handle.net/10459.1/465078
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/RTI2018-094739-B-I00
Reproducció del document publicat a: https://doi.org/10.1038/s41419-024-06492-1
Cell Death & Disease, 2024, vol. 15, num. 127
info:eu-repo/grantAgreement/EC/H2020/829010
dc.rights.none.fl_str_mv cc-by (c) Authors, 2024
info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-sa/4.0
rights_invalid_str_mv cc-by (c) Authors, 2024
https://creativecommons.org/licenses/by-sa/4.0
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Springer Nature
publisher.none.fl_str_mv Springer Nature
dc.source.none.fl_str_mv reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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