2026-05-17T01:16:01Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/261482025-12-18T12:53:33Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597
Repisalud
author
Lonardo, Enza
author
Hermann, Patrick C
author
Mueller, 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-Ruiz, 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
funder
Deutsche Krebshilfe
funder
European Research Council (ERC)
funder
Instituto de Salud Carlos III
funder
Ministerio de Ciencia e Innovación (España)
funder
Roche
2025-01-27T12:00:57Z
2025-01-27T12:00:57Z
2011-11-04
Cell Stem Cell . 2011 Nov 4;9(5):433-46.
Cell Stem Cell
22056140
https://hdl.handle.net/20.500.12105/26148
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.
eng
ACTIVIN-A
STELLATE-CELLS
TGF-BETA
HEDGEHOG PROMOTES
GROWTH-FACTOR
PATHWAYS
INHIBITION
PHENOTYPE
FIBROSIS
Nodal/Activin signaling drives self-renewal and tumorigenicity of pancreatic cancer stem cells and provides a target for combined drug therapy.
research article
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URL
https://repisalud.isciii.es/bitstreams/32a42c70-28f8-49d2-a511-7d3916826a45/download
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https://repisalud.isciii.es/bitstreams/3d553c9a-4259-4981-abc0-1c4e939e122c/download
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