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 Ian Murray, Raffaele A. Calogero, Cosimo De Bari, Peter S. Zammit, Mauro Delorenzi, Amy J. Wagers, Janet Shipley, Henning Wackerhage, Fernando D. Camargo*

*Corresponding author for this work

Research output: Contribution to journalArticle

80 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)273-287
Number of pages15
JournalCancer Cell
Volume26
Issue number2
DOIs
Publication statusPublished - 11 Aug 2014

Keywords

  • skeletal-muscle
  • stem-cells
  • gene-expression
  • growth-control
  • self-renewal
  • differentiation
  • transcription
  • pathway
  • MYOD
  • quiescent

Cite this

Tremblay, A. M., Missiaglia, E., Galli, G. G., Hettmer, S., Urcia, R., Carrara, M., ... Camargo, F. D. (2014). The Hippo Transducer YAP1 Transforms Activated Satellite Cells and Is a Potent Effector of Embryonal Rhabdomyosarcoma Formation. Cancer Cell, 26(2), 273-287. https://doi.org/10.1016/j.ccr.2014.05.029

The Hippo Transducer YAP1 Transforms Activated Satellite Cells and Is a Potent Effector of Embryonal Rhabdomyosarcoma Formation. / Tremblay, Annie M.; Missiaglia, Edoardo; Galli, Giorgio G.; Hettmer, Simone; Urcia, Roby; Carrara, Matteo; Judson, Robert N.; Thway, Khin; Nadal, Gema; Selfe, Joanna L.; Murray, Graeme Ian; Calogero, Raffaele A.; De Bari, Cosimo; Zammit, Peter S.; Delorenzi, Mauro; Wagers, Amy J.; Shipley, Janet; Wackerhage, Henning; Camargo, Fernando D.

In: Cancer Cell, Vol. 26, No. 2, 11.08.2014, p. 273-287.

Research output: Contribution to journalArticle

Tremblay, AM, Missiaglia, E, Galli, GG, Hettmer, S, Urcia, R, Carrara, M, Judson, RN, Thway, K, Nadal, G, Selfe, JL, Murray, GI, Calogero, RA, De Bari, C, Zammit, PS, Delorenzi, M, Wagers, AJ, Shipley, J, Wackerhage, H & Camargo, FD 2014, 'The Hippo Transducer YAP1 Transforms Activated Satellite Cells and Is a Potent Effector of Embryonal Rhabdomyosarcoma Formation', Cancer Cell, vol. 26, no. 2, pp. 273-287. https://doi.org/10.1016/j.ccr.2014.05.029
Tremblay, Annie M. ; Missiaglia, Edoardo ; Galli, Giorgio G. ; Hettmer, Simone ; Urcia, Roby ; Carrara, Matteo ; Judson, Robert N. ; Thway, Khin ; Nadal, Gema ; Selfe, Joanna L. ; Murray, Graeme Ian ; Calogero, Raffaele A. ; De Bari, Cosimo ; Zammit, Peter S. ; Delorenzi, Mauro ; Wagers, Amy J. ; Shipley, Janet ; Wackerhage, Henning ; Camargo, Fernando D. / The Hippo Transducer YAP1 Transforms Activated Satellite Cells and Is a Potent Effector of Embryonal Rhabdomyosarcoma Formation. In: Cancer Cell. 2014 ; Vol. 26, No. 2. pp. 273-287.
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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.",
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