Journal
CANCER CELL
Volume 26, Issue 2, Pages 273-287Publisher
CELL PRESS
DOI: 10.1016/j.ccr.2014.05.029
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Funding
- Stand Up to Cancer-AACR initiative
- NIH [AR064036, DK099559, DP2 OD004345-01]
- Canadian Institutes of Health Research (CIHR)
- Medical Research Council [99477]
- American-Italian Cancer Foundation
- Oliver Bird PhD studentship
- Friends of Anchor pilot grant
- Sarcoma UK
- Cancer Research UK [C5066/A10399]
- Chris Lucas Trust
- Stand Up to Cancer-AACR Innovative Research Grant [SU2C-AACR-IRG1111]
- P.A.L.S. Bermuda/St. Baldrick's and Alex's Lemonade Stand Foundation
- NHS
- [NIH-P50-NS40828]
- [NIH-P30-HD18655]
- Medical Research Council [G1100193] Funding Source: researchfish
- MRC [G1100193] Funding Source: UKRI
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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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