ZFIN ID: ZDB-PUB-170615-2
The NOTCH1/SNAIL1/MEF2C Pathway Regulates Growth and Self-Renewal in Embryonal Rhabdomyosarcoma
Ignatius, M.S., Hayes, M.N., Lobbardi, R., Chen, E.Y., McCarthy, K.M., Sreenivas, P., Motala, Z., Durbin, A.D., Molodtsov, A., Reeder, S., Jin, A., Sindiri, S., Beleyea, B.C., Bhere, D., Alexander, M.S., Shah, K., Keller, C., Linardic, C.M., Nielsen, P.G., Malkin, D., Khan, J., Langenau, D.M.
Date: 2017
Source: Cell Reports   19: 2304-2318 (Journal)
Registered Authors: Alexander, Matthew, Durbin, Adam, Hayes, Madeline, Ignatius, Myron, Langenau, David
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
PubMed: 28614716 Full text @ Cell Rep.
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.