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

Publication ,  Journal Article
Ignatius, MS; Hayes, MN; Lobbardi, R; Chen, EY; McCarthy, KM; Sreenivas, P; Motala, Z; Durbin, AD; Molodtsov, A; Reeder, S; Jin, A; Sindiri, S ...
Published in: Cell Rep
June 13, 2017

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.

Duke Scholars

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Published In

Cell Rep

DOI

EISSN

2211-1247

Publication Date

June 13, 2017

Volume

19

Issue

11

Start / End Page

2304 / 2318

Location

United States

Related Subject Headings

  • Zebrafish
  • Xenopus Proteins
  • Transcription Factors
  • Snail Family Transcription Factors
  • Signal Transduction
  • Rhabdomyosarcoma, Embryonal
  • Receptor, Notch1
  • MEF2 Transcription Factors
  • Humans
  • Cell Differentiation
 

Citation

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ICMJE
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Ignatius, M. S., Hayes, M. N., Lobbardi, R., Chen, E. Y., McCarthy, K. M., Sreenivas, P., … Langenau, D. M. (2017). The NOTCH1/SNAIL1/MEF2C Pathway Regulates Growth and Self-Renewal in Embryonal Rhabdomyosarcoma. Cell Rep, 19(11), 2304–2318. https://doi.org/10.1016/j.celrep.2017.05.061
Ignatius, Myron S., Madeline N. Hayes, Riadh Lobbardi, Eleanor Y. Chen, Karin M. McCarthy, Prethish Sreenivas, Zainab Motala, et al. “The NOTCH1/SNAIL1/MEF2C Pathway Regulates Growth and Self-Renewal in Embryonal Rhabdomyosarcoma.Cell Rep 19, no. 11 (June 13, 2017): 2304–18. https://doi.org/10.1016/j.celrep.2017.05.061.
Ignatius MS, Hayes MN, Lobbardi R, Chen EY, McCarthy KM, Sreenivas P, et al. The NOTCH1/SNAIL1/MEF2C Pathway Regulates Growth and Self-Renewal in Embryonal Rhabdomyosarcoma. Cell Rep. 2017 Jun 13;19(11):2304–18.
Ignatius, Myron S., et al. “The NOTCH1/SNAIL1/MEF2C Pathway Regulates Growth and Self-Renewal in Embryonal Rhabdomyosarcoma.Cell Rep, vol. 19, no. 11, June 2017, pp. 2304–18. Pubmed, doi:10.1016/j.celrep.2017.05.061.
Ignatius MS, Hayes MN, Lobbardi R, Chen EY, McCarthy KM, Sreenivas P, Motala Z, Durbin AD, Molodtsov A, Reeder S, Jin A, Sindiri S, Beleyea BC, Bhere D, Alexander MS, Shah K, Keller C, Linardic CM, Nielsen PG, Malkin D, Khan J, Langenau DM. The NOTCH1/SNAIL1/MEF2C Pathway Regulates Growth and Self-Renewal in Embryonal Rhabdomyosarcoma. Cell Rep. 2017 Jun 13;19(11):2304–2318.
Journal cover image

Published In

Cell Rep

DOI

EISSN

2211-1247

Publication Date

June 13, 2017

Volume

19

Issue

11

Start / End Page

2304 / 2318

Location

United States

Related Subject Headings

  • Zebrafish
  • Xenopus Proteins
  • Transcription Factors
  • Snail Family Transcription Factors
  • Signal Transduction
  • Rhabdomyosarcoma, Embryonal
  • Receptor, Notch1
  • MEF2 Transcription Factors
  • Humans
  • Cell Differentiation