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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

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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Hauptverfasser: Lonardo, Enza (VerfasserIn) , Hermann, Patrick C. (VerfasserIn) , Müller, Maria-Theresa (VerfasserIn) , Huber, Stephan (VerfasserIn) , Balic, Anamaria (VerfasserIn) , Miranda-Lorenzo, Irene (VerfasserIn) , Zagorac, Sladjana (VerfasserIn) , Alcala, Sonia (VerfasserIn) , Rodriguez-Arabaolaza, Iker (VerfasserIn) , Ramirez, Juan Carlos (VerfasserIn) , Torres-Ruíz, Raul (VerfasserIn) , Garcia, Elena (VerfasserIn) , Hidalgo, Manuel (VerfasserIn) , Cebrián, David Álvaro (VerfasserIn) , Heuchel, Rainer (VerfasserIn) , Löhr, Matthias (VerfasserIn) , Berger, Frank (VerfasserIn) , Bartenstein, Peter (VerfasserIn) , Aicher, Alexandra (VerfasserIn) , Heeschen, Christopher (VerfasserIn)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: November 4, 2011
In: Cell stem cell
Year: 2011, Jahrgang: 9, Heft: 5, Pages: 433-446
ISSN:1875-9777
DOI:10.1016/j.stem.2011.10.001
Online-Zugang:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.stem.2011.10.001
Verlag, lizenzpflichtig, Volltext: https://www.sciencedirect.com/science/article/pii/S1934590911004814
Volltext
Verfasserangaben:Enza Lonardo, Patrick C. Hermann, Maria-Theresa Mueller, Stephan Huber, Anamaria Balic, Irene Miranda-Lorenzo, Sladjana Zagorac, Sonia Alcala, Iker Rodriguez-Arabaolaza, Juan Carlos Ramirez, Raul Torres-Ruíz, Elena Garcia, Manuel Hidalgo, David Álvaro Cebrián, Rainer Heuchel, Matthias Löhr, Frank Berger, Peter Bartenstein, Alexandra Aicher, and Christopher Heeschen
Beschreibung
Zusammenfassung: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.
Beschreibung:Gesehen am 06.10.2022
Beschreibung:Online Resource
ISSN:1875-9777
DOI:10.1016/j.stem.2011.10.001

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