Snail regulates BMP and TGFβ pathways to control the differentiation status of glioma-initiating cells

Oncogene. 2018 May;37(19):2515-2531. doi: 10.1038/s41388-018-0136-0. Epub 2018 Feb 16.

Abstract

Glioblastoma multiforme is a brain malignancy characterized by high heterogeneity, invasiveness, and resistance to current therapies, attributes related to the occurrence of glioma stem cells (GSCs). Transforming growth factor β (TGFβ) promotes self-renewal and bone morphogenetic protein (BMP) induces differentiation of GSCs. BMP7 induces the transcription factor Snail to promote astrocytic differentiation in GSCs and suppress tumor growth in vivo. We demonstrate that Snail represses stemness in GSCs. Snail interacts with SMAD signaling mediators, generates a positive feedback loop of BMP signaling and transcriptionally represses the TGFB1 gene, decreasing TGFβ1 signaling activity. Exogenous TGFβ1 counteracts Snail function in vitro, and in vivo promotes proliferation and re-expression of Nestin, confirming the importance of TGFB1 gene repression by Snail. In conclusion, novel insight highlights mechanisms whereby Snail differentially regulates the activity of the opposing BMP and TGFβ pathways, thus promoting an astrocytic fate switch and repressing stemness in GSCs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Morphogenetic Proteins / metabolism
  • Brain Neoplasms / genetics
  • Brain Neoplasms / metabolism*
  • Cell Differentiation
  • Cell Line, Tumor
  • Gene Expression Profiling / methods*
  • Gene Expression Regulation, Neoplastic
  • Glioblastoma / genetics
  • Glioblastoma / metabolism*
  • Humans
  • Mice
  • Neoplasm Transplantation
  • Neoplastic Stem Cells / cytology*
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology
  • Signal Transduction*
  • Snail Family Transcription Factors / metabolism
  • Transforming Growth Factor beta / metabolism

Substances

  • Bone Morphogenetic Proteins
  • Snail Family Transcription Factors
  • Transforming Growth Factor beta