Cell Report: The NOTCH1/SNAIL1/MEF2C Pathway Regulates Growth and Self-Renewal in Embryonal Rhabdomyosarcoma

Myron S Ignatius 1Madeline N Hayes 2Riadh Lobbardi 2Eleanor Y Chen 3Karin M McCarthy 4Prethish Sreenivas 5Zainab Motala 6Adam D Durbin 7Aleksey Molodtsov 4Sophia Reeder 4Alexander Jin 4Sivasish Sindiri 8Brian C Beleyea 9Deepak Bhere 10Matthew S Alexander 11Khalid Shah 9Charles Keller 12Corinne M Linardic 8Petur G Nielsen 13David Malkin 6Javed Khan 8David M Langenau 14

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.

Keywords: MEF2C; NOTCH1; SNAI1; de-differentiation; muscle; rhabdomyosarcoma; self-renewal; tumor propagating cells; zebrafish.

Learn More Button

Article Categories: All News, Research Paper

Since 2004, UT Health San Antonio, Greehey Children’s Cancer Research Institute’s (Greehey CCRI) mission has been to advance scientific knowledge relevant to childhood cancer, contribute to understanding its causes, and accelerate the translation of knowledge into novel therapies. Greehey CCRI strives to have a national and global impact on childhood cancer by discovering, developing, and disseminating new scientific knowledge. Our mission consists of three key areas — research, clinical, and education.

Stay connected with the Greehey CCRI on Facebook, Twitter, LinkedIn, and Instagram.