title: The Hippo transducer YAP1 transforms activated satellite cells and is a potent effector of embryonal rhabdomyosarcoma formation.
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.
authors.affiliation: 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.
authors.forename: Annie M
authors.initials: AM
authors.lastname: Tremblay
authors.affiliation: 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.
authors.forename: Edoardo
authors.initials: E
authors.lastname: Missiaglia
authors.affiliation: 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.
authors.forename: Giorgio G
authors.initials: GG
authors.lastname: Galli
authors.affiliation: 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.
authors.forename: Simone
authors.initials: S
authors.lastname: Hettmer
authors.affiliation: School of Medical Sciences, University of Aberdeen, Aberdeen, AB25 2ZD Scotland, UK.
authors.forename: Roby
authors.initials: R
authors.lastname: Urcia
authors.affiliation: Molecular Biotechnology Center, Department of Biotechnology and Health Sciences, University of Torino, 10126 Torino, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Carrara
authors.affiliation: 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.
authors.forename: Robert N
authors.initials: RN
authors.lastname: Judson
authors.affiliation: 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.
authors.forename: Khin
authors.initials: K
authors.lastname: Thway
authors.affiliation: School of Medical Sciences, University of Aberdeen, Aberdeen, AB25 2ZD Scotland, UK.
authors.forename: Gema
authors.initials: G
authors.lastname: Nadal
authors.affiliation: Sarcoma Molecular Pathology Team, Divisions of Molecular Pathology and Cancer Therapeutics, The Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK.
authors.forename: Joanna L
authors.initials: JL
authors.lastname: Selfe
authors.affiliation: School of Medicine and Dentistry, University of Aberdeen, Aberdeen AB25 2ZD, Scotland, UK.
authors.forename: Graeme
authors.initials: G
authors.lastname: Murray
authors.affiliation: Molecular Biotechnology Center, Department of Biotechnology and Health Sciences, University of Torino, 10126 Torino, Italy.
authors.forename: Raffaele A
authors.initials: RA
authors.lastname: Calogero
authors.affiliation: School of Medicine and Dentistry, University of Aberdeen, Aberdeen AB25 2ZD, Scotland, UK.
authors.forename: Cosimo
authors.initials: C
authors.lastname: De Bari
authors.affiliation: Randall Division of Cell and Molecular Biophysics, King's College London, New Hunt's House, Guy's Campus, London SE1 1UL, UK.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Zammit
authors.affiliation: SIB Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland; Ludwig Center for Cancer Research and Oncology Department, University of Lausanne, 1015 Lausanne, Switzerland.
authors.forename: Mauro
authors.initials: M
authors.lastname: Delorenzi
authors.affiliation: 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.
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Wagers
authors.affiliation: Sarcoma Molecular Pathology Team, Divisions of Molecular Pathology and Cancer Therapeutics, The Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK.
authors.forename: Janet
authors.initials: J
authors.lastname: Shipley
authors.affiliation: School of Medical Sciences, University of Aberdeen, Aberdeen, AB25 2ZD Scotland, UK.
authors.forename: Henning
authors.initials: H
authors.lastname: Wackerhage
authors.affiliation: 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.
authors.forename: Fernando D
authors.initials: FD
authors.lastname: Camargo
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D018628:Gene Dosage; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D019042:Muscle Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D017570:MyoD Protein; D009368:Neoplasm Transplantation; D009687:Nuclear Proteins / Q000378:metabolism; D009857:Oncogenes; D010750:Phosphoproteins / Q000502:physiology*; D018233:Rhabdomyosarcoma, Embryonal / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D032496:Satellite Cells, Skeletal Muscle / Q000473:pathology*; D000091262:TEA Domain Transcription Factors; D014157:Transcription Factors / Q000378:metabolism; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; D017570:MyoD Protein; C057363:MyoD1 myogenic differentiation protein; D009687:Nuclear Proteins; D010750:Phosphoproteins; D000091262:TEA Domain Transcription Factors; C057182:TEAD1 protein, human; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human