TY - JOUR
T1 - Nodal/activin signaling drives self-renewal and tumorigenicity of pancreatic cancer stem cells and provides a target for combined drug therapy
AU - Lonardo, Enza
AU - Hermann, Patrick C.
AU - Mueller, Maria Theresa
AU - Huber, Stephan
AU - Balic, Anamaria
AU - Miranda-Lorenzo, Irene
AU - Zagorac, Sladjana
AU - Alcala, Sonia
AU - Rodriguez-Arabaolaza, Iker
AU - Ramirez, Juan Carlos
AU - Torres-Ruíz, Raul
AU - Garcia, Elena
AU - Hidalgo, Manuel
AU - Cebrián, David Álvaro
AU - Heuchel, Rainer
AU - Löhr, Matthias
AU - Berger, Frank
AU - Bartenstein, Peter
AU - Aicher, Alexandra
AU - Heeschen, Christopher
N1 - Funding Information:
We are indebted to Mercedes Alonso for excellent technical assistance and Francisco X. Real for providing primary tissue samples (both from the Spanish National Cancer Research Centre). This work was supported by the Dr. Mildred Scheel Foundation (108168), the ERC Advanced Investigator Grant (Pa-CSC 233460), the Subdirección General de Evaluación y Fomento de la Investigación, Fondo de Investigación Sanitaria (PS09/02129), and the Programa Nacional de Internacionalización de la I+D, Subprogramma: FCCI 2009 (PLE2009-0105; both Ministerio de Ciencia e Innovación, Spain). E.L. is supported by the Roche Postdoctoral Fellowship Program. Ludwig-Maximilian-University and the Spanish National Cancer Research Centre have filed a patent application for the use of the described treatment modality for epithelial cancer. The authors (E.L., M.T.M., P.C.H., S.H., and C.H.) are inventors of these patents, and may receive royalties from licensees.
Copyright:
Copyright 2012 Elsevier B.V., All rights reserved.
PY - 2011/11/4
Y1 - 2011/11/4
N2 - 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.
AB - 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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U2 - 10.1016/j.stem.2011.10.001
DO - 10.1016/j.stem.2011.10.001
M3 - Article
C2 - 22056140
AN - SCOPUS:80755141299
VL - 9
SP - 433
EP - 446
JO - Cell Stem Cell
JF - Cell Stem Cell
SN - 1934-5909
IS - 5
ER -