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

Annie M Tremblay; Edoardo Missiaglia; Giorgio G Galli; Simone Hettmer; Roby Urcia; Matteo Carrara; Robert N Judson; Khin Thway; Gema Nadal; Joanna L Selfe; Graeme Murray; Raffaele A Calogero; Cosimo De Bari; Peter S Zammit; Mauro Delorenzi; Amy J Wagers; Janet Shipley; Henning Wackerhage; Fernando D Camargo

doi:10.1016/j.ccr.2014.05.029

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

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

Authors

Annie M Tremblay¹, Edoardo Missiaglia², Giorgio G Galli¹, Simone Hettmer³, Roby Urcia⁴, Matteo Carrara⁵, Robert N Judson⁶, Khin Thway⁷, Gema Nadal⁴, Joanna L Selfe⁸, Graeme Murray⁹, Raffaele A Calogero⁵, Cosimo De Bari⁹, Peter S Zammit¹⁰, Mauro Delorenzi¹¹, Amy J Wagers¹², Janet Shipley⁸, Henning Wackerhage⁴, Fernando D Camargo¹³

Affiliations

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.

PMID: 25087979
DOI: 10.1016/j.ccr.2014.05.029

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing / physiology*
Animals
Cell Differentiation / genetics
Cell Proliferation
Cell Transformation, Neoplastic / metabolism*
DNA-Binding Proteins / metabolism
Gene Dosage
Gene Expression
Gene Expression Regulation, Neoplastic
Humans
Kaplan-Meier Estimate
Mice
Mice, Inbred NOD
Mice, SCID
Mice, Transgenic
Muscle Neoplasms / metabolism*
Muscle Neoplasms / mortality
Muscle Neoplasms / pathology
Muscle, Skeletal / metabolism
Muscle, Skeletal / pathology
MyoD Protein
Neoplasm Transplantation
Nuclear Proteins / metabolism
Oncogenes
Phosphoproteins / physiology*
Rhabdomyosarcoma, Embryonal / metabolism*
Rhabdomyosarcoma, Embryonal / mortality
Rhabdomyosarcoma, Embryonal / pathology
Satellite Cells, Skeletal Muscle / pathology*
TEA Domain Transcription Factors
Transcription Factors / metabolism
YAP-Signaling Proteins

Substances

Adaptor Proteins, Signal Transducing
DNA-Binding Proteins
MyoD Protein
MyoD1 myogenic differentiation protein
Nuclear Proteins
Phosphoproteins
TEA Domain Transcription Factors
TEAD1 protein, human
Transcription Factors
YAP-Signaling Proteins
YAP1 protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding