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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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-Ruiz, 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:Instituto de Salud Carlos III (ISCIII)
Repositorio:Repisalud
Idioma:inglés
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/26148
Acceso en línea:https://hdl.handle.net/20.500.12105/26148
Access Level:acceso abierto
Palabra clave:ACTIVIN-A
STELLATE-CELLS
TGF-BETA
HEDGEHOG PROMOTES
GROWTH-FACTOR
PATHWAYS
INHIBITION
PHENOTYPE
FIBROSIS
AGGRESSIVENESS
Descripción
Sumario: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.

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