Twist1 induces endothelial differentiation of tumour cells through the Jagged1-KLF4 axis

Nat Commun. 2014 Aug 22;5:4697. doi: 10.1038/ncomms5697.


The mechanisms controlling tumour-induced angiogenesis are presently not clear. In principle, angiogenesis can be achieved through the activation of endothelial cells in existing vessels or by transdifferentiation of tumour cells into endothelial cells. However, whether tumour cells can go through a prior epithelial-mesenchymal transition and further differentiate into endothelial cells remains unknown. Here we show that overexpression of Twist1, a transcriptional regulator that induces and promotes cancer metastasis, leads to endothelial differentiation in head and neck cancer (HNC) cells. Induction of Jagged1 expression by Twist1 is essential for Twist1-induced endothelial differentiation. The Jagged1/Notch signalling subsequently activates KLF4, inducing stem-like properties in HNC cells and conferring them with drug resistance. Our results indicate that the Twist1-Jagged1/KLF4 axis is essential both for transdifferentiation of tumour cells into endothelial cells and for chemoresistance acquisition.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium-Binding Proteins / genetics
  • Calcium-Binding Proteins / metabolism*
  • Cell Differentiation
  • Cell Line, Tumor / pathology
  • Cell Movement
  • Cell Transdifferentiation
  • Drug Resistance, Neoplasm
  • Endothelial Cells / metabolism
  • Endothelial Cells / pathology*
  • Female
  • Humans
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Jagged-1 Protein
  • Kruppel-Like Factor 4
  • Kruppel-Like Transcription Factors / genetics
  • Kruppel-Like Transcription Factors / metabolism*
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice, Inbred BALB C
  • Molecular Sequence Data
  • Neoplasms, Experimental / drug therapy
  • Neoplasms, Experimental / genetics
  • Neoplasms, Experimental / pathology
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Serrate-Jagged Proteins
  • Signal Transduction
  • Twist-Related Protein 1 / genetics
  • Twist-Related Protein 1 / metabolism*
  • Xenograft Model Antitumor Assays


  • Calcium-Binding Proteins
  • Intercellular Signaling Peptides and Proteins
  • JAG1 protein, human
  • Jag1 protein, mouse
  • Jagged-1 Protein
  • KLF4 protein, human
  • Klf4 protein, mouse
  • Kruppel-Like Factor 4
  • Kruppel-Like Transcription Factors
  • Membrane Proteins
  • Nuclear Proteins
  • Serrate-Jagged Proteins
  • TWIST1 protein, human
  • Twist-Related Protein 1

Associated data

  • GENBANK/GSE57756