Cell Stem Cell
Volume 9, Issue 5, 4 November 2011, Pages 433-446
Journal home page for Cell Stem Cell

Article
Nodal/Activin Signaling Drives Self-Renewal and Tumorigenicity of Pancreatic Cancer Stem Cells and Provides a Target for Combined Drug Therapy

https://doi.org/10.1016/j.stem.2011.10.001Get rights and content
Under an Elsevier user license
open archive

Summary

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.

Highlights

► Nodal and Activin drive the self-renewal capacity of pancreatic cancer stem cells ► Blocking the receptor Alk4/7 reverses the chemoresistance of cancer stem cells ► Inhibition in xenografted tumor explants is limited by drug accessibility ► Combined targeting of Alk4/7 and stroma gives long-term, progression-free survival

Cited by (0)