The NOTCH1/SNAIL1/MEF2C Pathway Regulates Growth and Self-Renewal in Embryonal Rhabdomyosarcoma

Cell Rep. 2017 Jun 13;19(11):2304-2318. doi: 10.1016/j.celrep.2017.05.061.


Tumor-propagating cells (TPCs) share self-renewal properties with normal stem cells and drive continued tumor growth. However, mechanisms regulating TPC self-renewal are largely unknown, especially in embryonal rhabdomyosarcoma (ERMS)-a common pediatric cancer of muscle. Here, we used a zebrafish transgenic model of ERMS to identify a role for intracellular NOTCH1 (ICN1) in increasing TPCs by 23-fold. ICN1 expanded TPCs by enabling the de-differentiation of zebrafish ERMS cells into self-renewing myf5+ TPCs, breaking the rigid differentiation hierarchies reported in normal muscle. ICN1 also had conserved roles in regulating human ERMS self-renewal and growth. Mechanistically, ICN1 upregulated expression of SNAIL1, a transcriptional repressor, to increase TPC number in human ERMS and to block muscle differentiation through suppressing MEF2C, a myogenic differentiation transcription factor. Our data implicate the NOTCH1/SNAI1/MEF2C signaling axis as a major determinant of TPC self-renewal and differentiation in ERMS, raising hope of therapeutically targeting this pathway in the future.

Keywords: MEF2C; NOTCH1; SNAI1; de-differentiation; muscle; rhabdomyosarcoma; self-renewal; tumor propagating cells; zebrafish.

MeSH terms

  • Animals
  • Cell Differentiation / physiology
  • Humans
  • MEF2 Transcription Factors / metabolism*
  • Receptor, Notch1 / metabolism*
  • Rhabdomyosarcoma, Embryonal / metabolism*
  • Rhabdomyosarcoma, Embryonal / pathology
  • Signal Transduction
  • Snail Family Transcription Factors / metabolism*
  • Transcription Factors / metabolism
  • Xenopus Proteins / metabolism
  • Zebrafish


  • MEF2 Transcription Factors
  • MEF2C protein, human
  • NOTCH1 protein, human
  • Receptor, Notch1
  • SNAI1 protein, human
  • Snai1 protein, Xenopus
  • Snail Family Transcription Factors
  • Transcription Factors
  • Xenopus Proteins