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

Cell Stem Cell. 2011 Nov 4;9(5):433-46. doi: 10.1016/j.stem.2011.10.001.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AC133 Antigen
  • Activins / metabolism*
  • Animals
  • Antigens, CD / metabolism
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Biomarkers, Tumor / metabolism
  • Cell Proliferation
  • Cell Transformation, Neoplastic / metabolism
  • Cell Transformation, Neoplastic / pathology*
  • Female
  • Gene Targeting
  • Glycoproteins / metabolism
  • Humans
  • Mice
  • Mice, Nude
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology*
  • Nodal Protein / metabolism*
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology*
  • Peptides / metabolism
  • Pluripotent Stem Cells / metabolism
  • Signal Transduction*
  • Spheroids, Cellular / metabolism
  • Spheroids, Cellular / pathology
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays


  • AC133 Antigen
  • Antigens, CD
  • Biomarkers, Tumor
  • Glycoproteins
  • Nodal Protein
  • Peptides
  • Activins