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.
Bibliographical noteWe thank Kriti Shrestha for technical assistance. This research was funded by a Stand Up to Cancer-AACR initiative grant (F.D.C.), NIH grants AR064036 (F.D.C.) and DK099559 (F.D.C.), a Canadian Institutes of Health Research (CIHR) fellowship (A.M.T.), a Medical Research Council project grant (99477, H.W., P.S.Z., C.D.B.), an American-Italian Cancer Foundation postdoctoral research fellowship (G.G.G.), an Oliver Bird PhD studentship (R.J.), a Friends of Anchor pilot grant and a Sarcoma UK grant (H.W., G.M., C.D.B.), a Cancer Research UK project grant (C5066/A10399) (J.S.), a Chris Lucas Trust grant (J.S.), a Stand Up to Cancer-AACR Innovative Research Grant (SU2C-AACR-IRG1111) and NIH New Innovator Award (DP2 OD004345-01) (A.J.W.), and grants from P.A.L.S. Bermuda/St. Baldrick’s and Alex’s Lemonade Stand Foundation (S.H.). Mouse microarray studies were performed by the Molecular Genetics Core Facility at Children’s Hospital Boston supported by NIH-P50-NS40828 and NIH-P30-HD18655. The Children’s Cancer and Leukemia Group, and UK and NHS funding to the NIHR Biomedical Research Centre, assisted with human tissue collection. Confocal imaging was performed at the Children’s Hospital Boston Imaging Core facility.
FingerprintDive into the research topics of 'The Hippo Transducer YAP1 Transforms Activated Satellite Cells and Is a Potent Effector of Embryonal Rhabdomyosarcoma Formation'. Together they form a unique fingerprint.
- School of Medicine, Medical Sciences & Nutrition, Applied Medicine - Clinical Chair in Experimental Medicine and Rheumatology
- School of Medicine, Medical Sciences & Nutrition, Molecular and Cellular Function
- School of Medicine, Medical Sciences & Nutrition, MRC/Versus Arthritis Centre for Musculoskeletal Health and Work
- School of Medicine, Medical Sciences & Nutrition, Institute of Medical Sciences
- School of Medicine, Medical Sciences & Nutrition, Aberdeen Centre for Arthritis and Musculoskeletal Health (ACAMH)
Person: Clinical Academic