NOTCH1/SNAIL1/MEF2C信号通路调控胚胎性横纹肌肉瘤的生长和自我更新。
The NOTCH1/SNAIL1/MEF2C Pathway Regulates Growth and Self-Renewal in Embryonal Rhabdomyosarcoma.
作者信息
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
机构信息
Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA; Center of Cancer Research, Massachusetts General Hospital, Charlestown, MA 02129, USA; Harvard Stem Cell Institute, Boston, MA 02114, USA; Greehey Children's Cancer Research Institute and Department of Molecular Medicine, UT Health Sciences Center, San Antonio, TX 78229, USA.
Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA; Center of Cancer Research, Massachusetts General Hospital, Charlestown, MA 02129, USA; Harvard Stem Cell Institute, Boston, MA 02114, USA.
出版信息
Cell Rep. 2017 Jun 13;19(11):2304-2318. doi: 10.1016/j.celrep.2017.05.061.
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.
肿瘤增殖细胞（TPCs）与正常干细胞具有自我更新特性，并驱动肿瘤持续生长。然而，调节TPC自我更新的机制在很大程度上尚不清楚，尤其是在胚胎性横纹肌肉瘤（ERMS）中，这是一种常见的儿童肌肉癌。在这里，我们使用ERMS的斑马鱼转基因模型来确定细胞内NOTCH1（ICN1）在将TPCs数量增加23倍方面的作用。ICN1通过使斑马鱼ERMS细胞去分化为自我更新的myf5+TPCs来扩大TPCs，打破了正常肌肉中报道的严格分化层次。ICN1在调节人类ERMS自我更新和生长方面也具有保守作用。从机制上讲，ICN1上调转录抑制因子SNAIL1的表达，以增加人类ERMS中的TPC数量，并通过抑制成肌分化转录因子MEF2C来阻断肌肉分化。我们的数据表明NOTCH1/SNAI1/MEF2C信号轴是ERMS中TPC自我更新和分化的主要决定因素，为未来针对该途径进行治疗带来了希望。
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