Nodal/activin signaling drives self-renewal and tumorigenicity of pancreatic cancer stem cells and provides a target for combined drug therapy

Enza Lonardo, Patrick C. Hermann, Maria Theresa Mueller, Stephan Huber, Anamaria Balic, Irene Miranda-Lorenzo, Sladjana Zagorac, Sonia Alcala, Iker Rodriguez-Arabaolaza, Juan Carlos Ramirez, Raul Torres-Ruíz, Elena Garcia, Manuel Hidalgo, David Álvaro Cebrián, Rainer Heuchel, Matthias Löhr, Frank Berger, Peter Bartenstein, Alexandra Aicher, Christopher Heeschen

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)433-446
Number of pages14
JournalCell Stem Cell
Volume9
Issue number5
DOIs
StatePublished - Nov 4 2011
Externally publishedYes

Fingerprint

Activins
Neoplastic Stem Cells
Pancreatic Neoplasms
gemcitabine
Drug Therapy
Pancreatic Stellate Cells
Activin Receptors
Embryonic Stem Cells
Disease-Free Survival
Pharmacology
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Medicine
  • Genetics

Cite this

Lonardo, E., Hermann, P. C., Mueller, M. T., Huber, S., Balic, A., Miranda-Lorenzo, I., ... Heeschen, C. (2011). Nodal/activin signaling drives self-renewal and tumorigenicity of pancreatic cancer stem cells and provides a target for combined drug therapy. Cell Stem Cell, 9(5), 433-446. https://doi.org/10.1016/j.stem.2011.10.001

Nodal/activin signaling drives self-renewal and tumorigenicity of pancreatic cancer stem cells and provides a target for combined drug therapy. / 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.

In: Cell Stem Cell, Vol. 9, No. 5, 04.11.2011, p. 433-446.

Research output: Contribution to journalArticle

Lonardo, E, Hermann, PC, Mueller, MT, Huber, S, Balic, A, Miranda-Lorenzo, I, Zagorac, S, Alcala, S, Rodriguez-Arabaolaza, I, Ramirez, JC, Torres-Ruíz, R, Garcia, E, Hidalgo, M, Cebrián, DÁ, Heuchel, R, Löhr, M, Berger, F, Bartenstein, P, Aicher, A & Heeschen, C 2011, 'Nodal/activin signaling drives self-renewal and tumorigenicity of pancreatic cancer stem cells and provides a target for combined drug therapy', Cell Stem Cell, vol. 9, no. 5, pp. 433-446. https://doi.org/10.1016/j.stem.2011.10.001
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. / Nodal/activin signaling drives self-renewal and tumorigenicity of pancreatic cancer stem cells and provides a target for combined drug therapy. In: Cell Stem Cell. 2011 ; Vol. 9, No. 5. pp. 433-446.
@article{570eb46778ad4d449eee01728062280d,
title = "Nodal/activin signaling drives self-renewal and tumorigenicity of pancreatic cancer stem cells and provides a target for combined drug therapy",
abstract = "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.",
author = "Enza Lonardo and Hermann, {Patrick C.} and Mueller, {Maria Theresa} and Stephan Huber and Anamaria Balic and Irene Miranda-Lorenzo and Sladjana Zagorac and Sonia Alcala and Iker Rodriguez-Arabaolaza and Ramirez, {Juan Carlos} and Raul Torres-Ru{\'i}z and Elena Garcia and Manuel Hidalgo and Cebri{\'a}n, {David {\'A}lvaro} and Rainer Heuchel and Matthias L{\"o}hr and Frank Berger and Peter Bartenstein and Alexandra Aicher and Christopher Heeschen",
year = "2011",
month = "11",
day = "4",
doi = "10.1016/j.stem.2011.10.001",
language = "English (US)",
volume = "9",
pages = "433--446",
journal = "Cell Stem Cell",
issn = "1934-5909",
publisher = "Cell Press",
number = "5",

}

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

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

U2 - 10.1016/j.stem.2011.10.001

DO - 10.1016/j.stem.2011.10.001

M3 - Article

VL - 9

SP - 433

EP - 446

JO - Cell Stem Cell

JF - Cell Stem Cell

SN - 1934-5909

IS - 5

ER -