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

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ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Cell Biology

Cite this

Lonardo, E., Hermann, P. C., Mueller, M. T., Huber, S., Balic, A., Miranda-Lorenzo, I., Zagorac, S., Alcala, S., Rodriguez-Arabaolaza, I., Ramirez, J. C., Torres-Ruíz, R., Garcia, E., Hidalgo, M., Cebrián, D. Á., 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, 9(5), 433-446. https://doi.org/10.1016/j.stem.2011.10.001