The NOTCH1/SNAIL1/MEF2C Pathway Regulates Growth and Self-Renewal in Embryonal Rhabdomyosarcoma.
The NOTCH1/SNAIL1/MEF2C Pathway Regulates Growth and Self-Renewal in Embryonal Rhabdomyosarcoma.
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DOI：
10.1016/j.celrep.2017.05.061
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发表时间：
2017-06-13
期刊：
影响因子：
8.8
通讯作者：
Langenau DM
中科院分区：
文献类型：
--
作者：
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
肿瘤增殖细胞（TPC）与正常干细胞共享自我更新特性，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是未知的，特别是在胚胎性横纹肌肉瘤（ERMS）-一种常见的儿科肌肉癌症。在这里，我们使用斑马鱼ERMS转基因模型来确定细胞内NOTCH 1（ICN 1）在增加TPC 23倍中的作用。ICN 1通过使斑马鱼ERMS细胞去分化为自我更新的myf 5 + TPC来扩增TPC，打破了正常肌肉中报道的严格分化等级。ICN 1在调节人ERMS自我更新和生长方面也具有保守的作用。从机制上讲，ICN 1上调转录抑制因子SNAIL 1的表达，以增加人ERMS中的TPC数量，并通过抑制成肌分化转录因子MEF 2C来阻断肌肉分化。我们的数据表明，NOTCH 1/SNAI 1/MEF 2C信号轴是TPC自我更新和ERMS分化的主要决定因素，这为将来治疗靶向这一途径带来了希望。肿瘤增殖细胞（TPC）驱动癌症生长，但调控TPC自我更新和维持的机制在很大程度上是未知的。Ignatius等人表明，NOTCH 1/SNAIL 1途径与RAS协同作用，以扩增胚胎性横纹肌肉瘤中的TPC。该途径阻断MEF 2C诱导的分化，并使ERMS细胞去分化为自我更新的TPC。
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. Tumor-propagating cells (TPCs) drive cancer growth, yet mechanisms regulating TPC self-renewal and maintenance are largely unknown. Ignatius et al. show that the NOTCH1/SNAIL1 pathway synergizes with RAS to expand TPCs in embryonal rhabdomyosarcoma. This pathway blocks MEF2C-induced differentiation and enables the de-differentiation of ERMS cells into self-renewing TPCs.
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影响因子：
64.5
作者：
Roesch A;Fukunaga-Kalabis M;Schmidt EC;Zabierowski SE;Brafford PA;Vultur A;Basu D;Gimotty P;Vogt T;Herlyn M
通讯作者：
Herlyn M
影响因子：
8
作者：
Satheesha S;Manzella G;Bovay A;Casanova EA;Bode PK;Belle R;Feuchtgruber S;Jaaks P;Dogan N;Koscielniak E;Schäfer BW
通讯作者：
Schäfer BW
影响因子：
64.8
作者：
Buczacki, Simon J. A.;Zecchini, Heather Ireland;Winton, Douglas J.
通讯作者：
Winton, Douglas J.
影响因子：
10.5
作者：
Timmerman, LA;Grego-Bessa, J;de la Pompa, JL
通讯作者：
de la Pompa, JL
影响因子：
64.8
作者：
Lafkas, Daniel;Shelton, Amy;Siebel, Christian W.
通讯作者：
Siebel, Christian W.