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oai:repisalud.isciii.es:20.500.12105/261482025-12-18T12:53:33Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597

00925njm 22002777a 4500 dc 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 author 2011-11-04 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. Cell Stem Cell . 2011 Nov 4;9(5):433-46. Cell Stem Cell 22056140 https://hdl.handle.net/20.500.12105/26148 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.