| Autor: |
Ignatius, Myron S., Hayes, Madeline N., Lobbardi, Riadh, Chen, Eleanor Y., McCarthy, Karin M., Sreenivas, Prethish, Motala, Zainab, Durbin, Adam D., Molodtsov, Aleksey, Reeder, Sophia, Jin, Alexander, Sindiri, Sivasish, Beleyea, Brian C., Bhere, Deepak, Alexander, Matthew S., Shah, Khalid, Keller, Charles, Linardic, Corinne M., Nielsen, Petur G., Malkin, David, Khan, Javed, Langenau, David M. |
| Zdroj: |
Cell Reports; June 2017, Vol. 19 Issue: 11 p2304-2318, 15p |
| Abstrakt: |
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/MEF2Csignaling axis as a major determinant of TPC self-renewal and differentiation in ERMS, raising hope of therapeutically targeting this pathway in the future. |
| Databáze: |
Supplemental Index |
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