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-b 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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Detalles Bibliográficos
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-Ruíz, 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:Universidad Camilo José Cela (UCJC)
Repositorio:Depósito Digital e-UCJC
OAI Identifier:oai:repositorio.ucjc.edu:20.500.12020/1582
Acceso en línea:http://hdl.handle.net/20.500.12020/1582
https://doi.org/10.1016/j.stem.2011.10.001
Access Level:acceso abierto
Palabra clave:Biología Celular y Molecular
Pancreatic Cancer
Cancer Stem Cell
32 Ciencias Médicas
Descripción
Sumario:Nodal and Activin belong to the TGF-b 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-b. 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 longterm, progression-free survival. Therefore, inhibition of the Alk4/7 pathway, if combined with hedgehog pathway inhibition andgemcitabine, provides atherapeutic strategy for targeting cancer stem cells.

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