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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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Main Authors: Lonardo, Enza (Author) , Hermann, Patrick C. (Author) , Müller, Maria-Theresa (Author) , Huber, Stephan (Author) , Balic, Anamaria (Author) , Miranda-Lorenzo, Irene (Author) , Zagorac, Sladjana (Author) , Alcala, Sonia (Author) , Rodriguez-Arabaolaza, Iker (Author) , Ramirez, Juan Carlos (Author) , Torres-Ruíz, Raul (Author) , Garcia, Elena (Author) , Hidalgo, Manuel (Author) , Cebrián, David Álvaro (Author) , Heuchel, Rainer (Author) , Löhr, Matthias (Author) , Berger, Frank (Author) , Bartenstein, Peter (Author) , Aicher, Alexandra (Author) , Heeschen, Christopher (Author)
Format: Article (Journal)
Language:English
Published: November 4, 2011
In: Cell stem cell
Year: 2011, Volume: 9, Issue: 5, Pages: 433-446
ISSN:1875-9777
DOI:10.1016/j.stem.2011.10.001
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.stem.2011.10.001
Verlag, lizenzpflichtig, Volltext: https://www.sciencedirect.com/science/article/pii/S1934590911004814
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Author Notes: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
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Summary: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.
Item Description:Gesehen am 06.10.2022
Physical Description:Online Resource
ISSN:1875-9777
DOI:10.1016/j.stem.2011.10.001

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