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

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dc.contributor.authorLonardo, Enza
dc.contributor.authorHermann, Patrick C
dc.contributor.authorMueller, Maria-Theresa
dc.contributor.authorHuber, Stephan
dc.contributor.authorBalic, Anamaria
dc.contributor.authorMiranda-Lorenzo, Irene
dc.contributor.authorZagorac, Sladjana
dc.contributor.authorAlcala, Sonia
dc.contributor.authorRodriguez-Arabaolaza, Iker
dc.contributor.authorRamirez, Juan Carlos
dc.contributor.authorTorres-Ruiz, Raul
dc.contributor.authorGarcia, Elena
dc.contributor.authorHidalgo, Manuel
dc.contributor.authorCebrián, David Álvaro
dc.contributor.authorHeuchel, Rainer
dc.contributor.authorLöhr, Matthias
dc.contributor.authorBerger, Frank
dc.contributor.authorBartenstein, Peter
dc.contributor.authorAicher, Alexandra
dc.contributor.authorHeeschen, Christopher
dc.contributor.funderDeutsche Krebshilfe
dc.contributor.funderEuropean Research Council (ERC)
dc.contributor.funderInstituto de Salud Carlos III
dc.contributor.funderMinisterio de Ciencia e Innovación (España)
dc.contributor.funderRoche
dc.date.accessioned2025-01-27T12:00:57Z
dc.date.available2025-01-27T12:00:57Z
dc.date.issued2011-11-04
dc.descriptionWe are indebted to Mercedes Alonso for excellent technical assistance and Francisco X. Real for providing primary tissue samples (both from the Spanish National Cancer Research Centre). This work was supported by the Dr. Mildred Scheel Foundation (108168), the ERC Advanced Investigator Grant (Pa-CSC 233460), the Subdireccion General de Evaluacion y Fomento de la Investigacion, Fondo de Investigacion Sanitaria (PS09/02129), and the Programa Nacional de Internacionalizacion de la I+D, Subprogramma: FCCI 2009 (PLE2009-0105; both Ministerio de Ciencia e Innovacion, Spain). E.L. is supported by the Roche Postdoctoral Fellowship Program. Ludwig-Maximilian-University and the Spanish National Cancer Research Centre have filed a patent application for the use of the described treatment modality for epithelial cancer. The authors (E.L., M.T.M., P.C.H., S.H., and C.H.) are inventors of these patents, and may receive royalties from licensees.
dc.description.abstractNodal 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.
dc.description.peerreviewedSí
dc.format.number5
dc.format.page433-446
dc.format.volume9
dc.identifier.citationCell Stem Cell . 2011 Nov 4;9(5):433-46.
dc.identifier.journalCell Stem Cell
dc.identifier.pubmedID22056140
dc.identifier.urihttps://hdl.handle.net/20.500.12105/26148
dc.language.isoeng
dc.publisherCell Press
dc.relation.projectIDinfo:eu-repo/grantAgreement/MICINN//PS09%2F02129/ES/MOLECULAR CHARACTERIZATION OF CANCER (STEM) CELLS FOR THE DEVELOPMENT OF NOVEL TARGETED TREATMENTS MODALITIES/
dc.relation.projectID2
dc.relation.publisherversionhttps://doi: 10.1016/j.stem.2011.10.001.
dc.repisalud.institucionCNIO
dc.repisalud.orgCNIOCNIO::Unidades técnicas::Unidad de Citogenética Molecular
dc.rights.accessRightsopen access
dc.rights.licenseAttribution-NonCommercial-NoDerivatives 4.0 International
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subjectACTIVIN-A
dc.subjectSTELLATE-CELLS
dc.subjectTGF-BETA
dc.subjectHEDGEHOG PROMOTES
dc.subjectGROWTH-FACTOR
dc.subjectPATHWAYS
dc.subjectINHIBITION
dc.subjectPHENOTYPE
dc.subjectFIBROSIS
dc.subject.meshAGGRESSIVENESS
dc.titleNodal/Activin signaling drives self-renewal and tumorigenicity of pancreatic cancer stem cells and provides a target for combined drug therapy.
dc.typeresearch article
dc.type.hasVersionVoR
dspace.entity.typePublication
relation.isAuthorOfPublication6c54780c-068e-41c2-9f5d-ec932cd52d04
relation.isAuthorOfPublication.latestForDiscovery6c54780c-068e-41c2-9f5d-ec932cd52d04

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