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
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.
UR - http://www.scopus.com/inward/record.url?scp=80755141299&partnerID=8YFLogxK
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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 -