Nodal/Activin signaling drives self-renewal and tumorigenicity of pancreatic cancer stem cells and provides a target for combined drug therapy.

Nodal and Activin belong to the TGF-β superfamily and are important regulators of embryonic stem cell fate. Here we investigated whether Nodal and Activin regulate self-renewal of pancreatic cancer stem cells. Nodal and Activin were hardly detectable in more differentiated pancreatic cancer cells, w...

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Autores: Lonardo, Enza, Hermann, Patrick C, Mueller, Maria-Theresa, Huber, Stephan, Balic, Anamaria, Miranda-Lorenzo, Irene, Zagorac, Sladjana, Alcala, Sonia, Rodriguez-Arabaolaza, Iker, Ramirez, Juan Carlos, Torres-Ruiz, Raul, Garcia, Elena, Hidalgo, Manuel, Cebrián, David Álvaro, Heuchel, Rainer, Löhr, Matthias, Berger, Frank, Bartenstein, Peter, Aicher, Alexandra, Heeschen, Christopher
Tipo de recurso: artículo
Fecha de publicación:2011
País:España
Institución:Instituto de Salud Carlos III (ISCIII)
Repositorio:Repisalud
Idioma:inglés
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/26148
Acceso en línea:https://hdl.handle.net/20.500.12105/26148
Access Level:acceso abierto
Palabra clave:ACTIVIN-A
STELLATE-CELLS
TGF-BETA
HEDGEHOG PROMOTES
GROWTH-FACTOR
PATHWAYS
INHIBITION
PHENOTYPE
FIBROSIS
AGGRESSIVENESS
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repository_id_str
spelling Nodal/Activin signaling drives self-renewal and tumorigenicity of pancreatic cancer stem cells and provides a target for combined drug therapy.Lonardo, EnzaHermann, Patrick CMueller, Maria-TheresaHuber, StephanBalic, AnamariaMiranda-Lorenzo, IreneZagorac, SladjanaAlcala, SoniaRodriguez-Arabaolaza, IkerRamirez, Juan CarlosTorres-Ruiz, RaulGarcia, ElenaHidalgo, ManuelCebrián, David ÁlvaroHeuchel, RainerLöhr, MatthiasBerger, FrankBartenstein, PeterAicher, AlexandraHeeschen, ChristopherACTIVIN-ASTELLATE-CELLSTGF-BETAHEDGEHOG PROMOTESGROWTH-FACTORPATHWAYSINHIBITIONPHENOTYPEFIBROSISAGGRESSIVENESSNodal and Activin belong to the TGF-β superfamily and are important regulators of embryonic stem cell fate. Here we investigated whether Nodal and Activin regulate self-renewal of pancreatic cancer stem cells. Nodal and Activin were hardly detectable in more differentiated pancreatic cancer cells, while cancer stem cells and stroma-derived pancreatic stellate cells markedly overexpressed Nodal and Activin, but not TGF-β. Knockdown or pharmacological inhibition of the Nodal/Activin receptor Alk4/7 in cancer stem cells virtually abrogated their self-renewal capacity and in vivo tumorigenicity, and reversed the resistance of orthotopically engrafted cancer stem cells to gemcitabine. However, engrafted primary human pancreatic cancer tissue with a substantial stroma showed no response due to limited drug delivery. The addition of a stroma-targeting hedgehog pathway inhibitor enhanced delivery of the Nodal/Activin inhibitor and translated into long-term, progression-free survival. Therefore, inhibition of the Alk4/7 pathway, if combined with hedgehog pathway inhibition and gemcitabine, provides a therapeutic strategy for targeting cancer stem cells.Cell PressDeutsche KrebshilfeEuropean Research Council (ERC)Instituto de Salud Carlos IIIMinisterio de Ciencia e Innovación (España)Roche20252025-01-2720112011-11-0420112011-11-04research articlehttp://purl.org/coar/resource_type/c_2df8fbb1VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfapplication/pdfhttps://hdl.handle.net/20.500.12105/26148reponame:Repisaludinstname:Instituto de Salud Carlos III (ISCIII)InglésengMinisterio de Ciencia e Innovación http://dx.doi.org/10.13039/501100004837 Not available PS09%2F02129 MOLECULAR CHARACTERIZATION OF CANCER (STEM) CELLS FOR THE DEVELOPMENT OF NOVEL TARGETED TREATMENTS MODALITIESopen accesshttp://purl.org/coar/access_right/c_abf2Attribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:repisalud.isciii.es:20.500.12105/261482026-06-12T12:43:37Z
dc.title.none.fl_str_mv Nodal/Activin signaling drives self-renewal and tumorigenicity of pancreatic cancer stem cells and provides a target for combined drug therapy.
title Nodal/Activin signaling drives self-renewal and tumorigenicity of pancreatic cancer stem cells and provides a target for combined drug therapy.
spellingShingle Nodal/Activin signaling drives self-renewal and tumorigenicity of pancreatic cancer stem cells and provides a target for combined drug therapy.
Lonardo, Enza
ACTIVIN-A
STELLATE-CELLS
TGF-BETA
HEDGEHOG PROMOTES
GROWTH-FACTOR
PATHWAYS
INHIBITION
PHENOTYPE
FIBROSIS
AGGRESSIVENESS
title_short Nodal/Activin signaling drives self-renewal and tumorigenicity of pancreatic cancer stem cells and provides a target for combined drug therapy.
title_full Nodal/Activin signaling drives self-renewal and tumorigenicity of pancreatic cancer stem cells and provides a target for combined drug therapy.
title_fullStr Nodal/Activin signaling drives self-renewal and tumorigenicity of pancreatic cancer stem cells and provides a target for combined drug therapy.
title_full_unstemmed Nodal/Activin signaling drives self-renewal and tumorigenicity of pancreatic cancer stem cells and provides a target for combined drug therapy.
title_sort Nodal/Activin signaling drives self-renewal and tumorigenicity of pancreatic cancer stem cells and provides a target for combined drug therapy.
dc.creator.none.fl_str_mv Lonardo, Enza
Hermann, Patrick C
Mueller, Maria-Theresa
Huber, Stephan
Balic, Anamaria
Miranda-Lorenzo, Irene
Zagorac, Sladjana
Alcala, Sonia
Rodriguez-Arabaolaza, Iker
Ramirez, Juan Carlos
Torres-Ruiz, Raul
Garcia, Elena
Hidalgo, Manuel
Cebrián, David Álvaro
Heuchel, Rainer
Löhr, Matthias
Berger, Frank
Bartenstein, Peter
Aicher, Alexandra
Heeschen, Christopher
author Lonardo, Enza
author_facet Lonardo, Enza
Hermann, Patrick C
Mueller, Maria-Theresa
Huber, Stephan
Balic, Anamaria
Miranda-Lorenzo, Irene
Zagorac, Sladjana
Alcala, Sonia
Rodriguez-Arabaolaza, Iker
Ramirez, Juan Carlos
Torres-Ruiz, Raul
Garcia, Elena
Hidalgo, Manuel
Cebrián, David Álvaro
Heuchel, Rainer
Löhr, Matthias
Berger, Frank
Bartenstein, Peter
Aicher, Alexandra
Heeschen, Christopher
author_role author
author2 Hermann, Patrick C
Mueller, Maria-Theresa
Huber, Stephan
Balic, Anamaria
Miranda-Lorenzo, Irene
Zagorac, Sladjana
Alcala, Sonia
Rodriguez-Arabaolaza, Iker
Ramirez, Juan Carlos
Torres-Ruiz, Raul
Garcia, Elena
Hidalgo, Manuel
Cebrián, David Álvaro
Heuchel, Rainer
Löhr, Matthias
Berger, Frank
Bartenstein, Peter
Aicher, Alexandra
Heeschen, Christopher
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Deutsche Krebshilfe
European Research Council (ERC)
Instituto de Salud Carlos III
Ministerio de Ciencia e Innovación (España)
Roche
dc.subject.none.fl_str_mv ACTIVIN-A
STELLATE-CELLS
TGF-BETA
HEDGEHOG PROMOTES
GROWTH-FACTOR
PATHWAYS
INHIBITION
PHENOTYPE
FIBROSIS
AGGRESSIVENESS
topic ACTIVIN-A
STELLATE-CELLS
TGF-BETA
HEDGEHOG PROMOTES
GROWTH-FACTOR
PATHWAYS
INHIBITION
PHENOTYPE
FIBROSIS
AGGRESSIVENESS
description Nodal and Activin belong to the TGF-β superfamily and are important regulators of embryonic stem cell fate. Here we investigated whether Nodal and Activin regulate self-renewal of pancreatic cancer stem cells. Nodal and Activin were hardly detectable in more differentiated pancreatic cancer cells, while cancer stem cells and stroma-derived pancreatic stellate cells markedly overexpressed Nodal and Activin, but not TGF-β. Knockdown or pharmacological inhibition of the Nodal/Activin receptor Alk4/7 in cancer stem cells virtually abrogated their self-renewal capacity and in vivo tumorigenicity, and reversed the resistance of orthotopically engrafted cancer stem cells to gemcitabine. However, engrafted primary human pancreatic cancer tissue with a substantial stroma showed no response due to limited drug delivery. The addition of a stroma-targeting hedgehog pathway inhibitor enhanced delivery of the Nodal/Activin inhibitor and translated into long-term, progression-free survival. Therefore, inhibition of the Alk4/7 pathway, if combined with hedgehog pathway inhibition and gemcitabine, provides a therapeutic strategy for targeting cancer stem cells.
publishDate 2011
dc.date.none.fl_str_mv 2011
2011-11-04
2011
2011-11-04
2025
2025-01-27
dc.type.none.fl_str_mv research article
http://purl.org/coar/resource_type/c_2df8fbb1
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://hdl.handle.net/20.500.12105/26148
url https://hdl.handle.net/20.500.12105/26148
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.relation.none.fl_str_mv Ministerio de Ciencia e Innovación http://dx.doi.org/10.13039/501100004837 Not available PS09%2F02129 MOLECULAR CHARACTERIZATION OF CANCER (STEM) CELLS FOR THE DEVELOPMENT OF NOVEL TARGETED TREATMENTS MODALITIES
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution-NonCommercial-NoDerivatives 4.0 International
http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution-NonCommercial-NoDerivatives 4.0 International
http://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Cell Press
publisher.none.fl_str_mv Cell Press
dc.source.none.fl_str_mv reponame:Repisalud
instname:Instituto de Salud Carlos III (ISCIII)
instname_str Instituto de Salud Carlos III (ISCIII)
reponame_str Repisalud
collection Repisalud
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869406957869203456
score 15.812429

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