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Cancer Cell. 2014 Aug 11;26(2):273-87. doi: 10.1016/j.ccr.2014.05.029. Epub 2014 Jul 31.

The Hippo transducer YAP1 transforms activated satellite cells and is a potent effector of embryonal rhabdomyosarcoma formation.

Author information

1
Stem Cell Program, Boston Children's Hospital, Boston, MA 02115, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA.
2
SIB Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland; Sarcoma Molecular Pathology Team, Divisions of Molecular Pathology and Cancer Therapeutics, The Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK.
3
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Howard Hughes Medical Institute and Joslin Diabetes Center, Boston, MA 02115, USA; Department of Pediatric Oncology, Dana Farber Cancer Institute, Boston, MA 02115, USA; Division of Pediatric Hematology/Oncology, Children's Hospital, Boston, MA 02115, USA.
4
School of Medical Sciences, University of Aberdeen, Aberdeen, AB25 2ZD Scotland, UK.
5
Molecular Biotechnology Center, Department of Biotechnology and Health Sciences, University of Torino, 10126 Torino, Italy.
6
School of Medical Sciences, University of Aberdeen, Aberdeen, AB25 2ZD Scotland, UK; Biomedical Research Centre, Department of Medical Genetics, University of British Columbia, Vancouver BC V6T 1Z3, Canada.
7
Sarcoma Molecular Pathology Team, Divisions of Molecular Pathology and Cancer Therapeutics, The Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK; Department of Histopathology, Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK.
8
Sarcoma Molecular Pathology Team, Divisions of Molecular Pathology and Cancer Therapeutics, The Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK.
9
School of Medicine and Dentistry, University of Aberdeen, Aberdeen AB25 2ZD, Scotland, UK.
10
Randall Division of Cell and Molecular Biophysics, King's College London, New Hunt's House, Guy's Campus, London SE1 1UL, UK.
11
SIB Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland; Ludwig Center for Cancer Research and Oncology Department, University of Lausanne, 1015 Lausanne, Switzerland.
12
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Howard Hughes Medical Institute and Joslin Diabetes Center, Boston, MA 02115, USA.
13
Stem Cell Program, Boston Children's Hospital, Boston, MA 02115, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA. Electronic address: fernando.camargo@childrens.harvard.edu.

Abstract

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.

PMID:
25087979
DOI:
10.1016/j.ccr.2014.05.029
[Indexed for MEDLINE]
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