Ignatius, Myron S.Hayes, MadelineLobbardi, RiadhChen, Eleanor Y.McCarthy, Karin M.Sreenivas, PrethishMotala, ZainabDurbin, AdamMolodtsov, AlekseyReeder, SophiaJin, AlexanderSindiri, SivasishBeleyea, Brian C.Bhere, DeepakAlexander, Matthew S.Shah, KhalidKeller, CharlesLinardic, Corinne M.Nielsen, Petur G.Malkin, DavidKhan, JavedLangenau, David2017-11-212017Ignatius, M. S., M. N. Hayes, R. Lobbardi, E. Y. Chen, K. M. McCarthy, P. Sreenivas, Z. Motala, et al. 2017. “The NOTCH1/SNAIL1/MEF2C Pathway Regulates Growth and Self-Renewal in Embryonal Rhabdomyosarcoma.” Cell reports 19 (11): 2304-2318. doi:10.1016/j.celrep.2017.05.061. http://dx.doi.org/10.1016/j.celrep.2017.05.061.http://nrs.harvard.edu/urn-3:HUL.InstRepos:34375053Summary 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 up-regulated 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.en-USJournal Article2017-11-2110.1016/j.celrep.2017.05.061