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 language | English |
|---|---|
| Pages (from-to) | 273-287 |
| Number of pages | 15 |
| Journal | Cancer Cell |
| Volume | 26 |
| Issue number | 2 |
| DOIs | |
| Publication status | Published - 11 Aug 2014 |
Keywords
- skeletal-muscle
- stem-cells
- gene-expression
- growth-control
- self-renewal
- differentiation
- transcription
- pathway
- MYOD
- quiescent
Cite this
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 journal › Article
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TY - JOUR
T1 - The Hippo Transducer YAP1 Transforms Activated Satellite Cells and Is a Potent Effector of Embryonal Rhabdomyosarcoma Formation
AU - Tremblay, Annie M.
AU - Missiaglia, Edoardo
AU - Galli, Giorgio G.
AU - Hettmer, Simone
AU - Urcia, Roby
AU - Carrara, Matteo
AU - Judson, Robert N.
AU - Thway, Khin
AU - Nadal, Gema
AU - Selfe, Joanna L.
AU - Murray, Graeme Ian
AU - Calogero, Raffaele A.
AU - De Bari, Cosimo
AU - Zammit, Peter S.
AU - Delorenzi, Mauro
AU - Wagers, Amy J.
AU - Shipley, Janet
AU - Wackerhage, Henning
AU - Camargo, Fernando D.
PY - 2014/8/11
Y1 - 2014/8/11
N2 - 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.
AB - 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.
KW - skeletal-muscle
KW - stem-cells
KW - gene-expression
KW - growth-control
KW - self-renewal
KW - differentiation
KW - transcription
KW - pathway
KW - MYOD
KW - quiescent
U2 - 10.1016/j.ccr.2014.05.029
DO - 10.1016/j.ccr.2014.05.029
M3 - Article
VL - 26
SP - 273
EP - 287
JO - Cancer Cell
JF - Cancer Cell
SN - 1535-6108
IS - 2
ER -