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

Academic Article

Abstract

  • 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.
  • Published In

  • Cell Reports  Journal
  • Keywords

  • MEF2C, NOTCH1, SNAI1, de-differentiation, muscle, rhabdomyosarcoma, self-renewal, tumor propagating cells, zebrafish, Animals, Cell Differentiation, Humans, MEF2 Transcription Factors, Receptor, Notch1, Rhabdomyosarcoma, Embryonal, Signal Transduction, Snail Family Transcription Factors, Transcription Factors, Xenopus Proteins, Zebrafish
  • Digital Object Identifier (doi)

    Authorlist

  • Ignatius MS; Hayes MN; Lobbardi R; Chen EY; McCarthy KM; Sreenivas P; Motala Z; Durbin AD; Molodtsov A; Reeder S
  • Start Page

  • 2304
  • End Page

  • 2318
  • Volume

  • 19
  • Issue

  • 11