The Hippo Transducer YAP1 Transforms Activated Satellite Cells and Is a Potent Effector of Embryonal Rhabdomyosarcoma Formation

被引：156

作者：

Tremblay, Annie M. ^{[1
,2
,3
]}

Missiaglia, Edoardo ^{[4
,5
,6
]}

Galli, Giorgio G. ^{[1
,2
,3
]}

Hettmer, Simone ^{[2
,3
,10
,11
,12
,13
]}

Urcia, Roby ^{[8
]}

Carrara, Matteo ^{[17
]}

Judson, Robert N. ^{[8
,18
]}

Thway, Khin ^{[5
,6
,7
]}

Nadal, Gema ^{[8
]}

Selfe, Joanna L. ^{[5
,6
]}

Murray, Graeme ^{[9
]}

Calogero, Raffaele A. ^{[17
]}

De Bari, Cosimo ^{[9
]}

Zammit, Peter S. ^{[14
]}

Delorenzi, Mauro ^{[4
,15
,16
]}

Wagers, Amy J. ^{[2
,3
,10
,11
]}

Shipley, Janet ^{[5
,6
]}

Wackerhage, Henning ^{[8
]}

Camargo, Fernando D. ^{[1
,2
,3
]}

机构：

[1] Boston Childrens Hosp, Stem Cell Program, Boston, MA 02115 USA

[2] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA

[3] Harvard Stem Cell Inst, Cambridge, MA 02138 USA

[4] SIB Swiss Inst Bioinformat, CH-1015 Lausanne, Switzerland

[5] Inst Canc Res, Sarcoma Mol Pathol Team, Div Mol Pathol, Sutton SM2 5NG, Surrey, England

[6] Inst Canc Res, Sarcoma Mol Pathol Team, Div Canc Therapeut, Sutton SM2 5NG, Surrey, England

[7] Royal Marsden NHS Fdn Trust, Dept Histopathol, London SW3 6JJ, England

[8] Univ Aberdeen, Sch Med Sci, Aberdeen AB25 2ZD, Scotland

[9] Univ Aberdeen, Sch Med & Dent, Aberdeen AB25 2ZD, Scotland

[10] Howard Hughes Med Inst, Boston, MA 02115 USA

[11] Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02115 USA

[12] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA

[13] Childrens Hosp, Div Pediat Hematol Oncol, Boston, MA 02115 USA

[14] Kings Coll London, Randall Div Cell & Mol Biophys, London SE1 1UL, England

[15] Univ Lausanne, Ludwig Ctr Canc Res, CH-1015 Lausanne, Switzerland

[16] Univ Lausanne, Dept Oncol, CH-1015 Lausanne, Switzerland

[17] Univ Torino, Dept Biotechnol & Hlth Sci, Ctr Mol Biotechnol, I-10126 Turin, Italy

[18] Univ British Columbia, Dept Med Genet, Biomed Res Ctr, Vancouver, BC V6T 1Z3, Canada

来源：

CANCER CELL | 2014年 / 26卷 / 02期

基金：

英国医学研究理事会; 加拿大健康研究院;

关键词：

SKELETAL-MUSCLE; STEM-CELLS; GENE-EXPRESSION; GROWTH-CONTROL; SELF-RENEWAL; MYOD; DIFFERENTIATION; TRANSCRIPTION; PATHWAY; QUIESCENT;

D O I：

10.1016/j.ccr.2014.05.029

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

The role of the Hippo pathway effector YAP1 in soft tissue sarcomas is poorly defined. Here we report that YAP1 activity is elevated in human embryonal rhabdomyosarcoma (ERMS). In mice, sustained YAP1 hyperactivity in activated, but not quiescent, satellite cells induces ERMS with high penetrance and short latency. Via its transcriptional program with TEAD1, YAP1 directly regulates several major hallmarks of ERMS. YAP1-TEAD1 upregulate pro-proliferative and oncogenic genes and maintain the ERMS differentiation block by interfering with MYOD1 and MEF2 pro-differentiation activities. Normalization of YAP1 expression reduces tumor burden in human ERMS xenografts and allows YAP1-driven ERMS to differentiate in situ. Collectively, our results identify YAP1 as a potent ERMS oncogenic driver and a promising target for differentiation therapy.

引用

页码：273 / 287

页数：15

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