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XB-ART-54815
Cell Rep January 1, 2017; 19 (11): 2304-2318.

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

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 .


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.

PubMed ID: 28614716
PMC ID: PMC5563075
Article link: Cell Rep
Grant support: [+]

Species referenced: Xenopus
Genes referenced: ctrl hes1 hey1 kidins220 mef2c myf5 notch1 notch3 runx1 sms snai1 snai2 tbp


Article Images: [+] show captions
References [+] :
Beck, Unravelling cancer stem cell potential. 2013, Pubmed