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

doi:10.1016/j.ccr.2014.05.029

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 journal › Article › peer-review

146 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 language	English
Pages (from-to)	273-287
Number of pages	15
Journal	Cancer Cell
Volume	26
Issue number	2
Early online date	31 Jul 2014
DOIs	https://doi.org/10.1016/j.ccr.2014.05.029
Publication status	Published - 11 Aug 2014

Bibliographical note

We 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.

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Cosimo De Bari
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Tremblay, A. M., Missiaglia, E., Galli, G. G., Hettmer, S., Urcia, R., Carrara, M., Judson, R. N., Thway, K., Nadal, G., Selfe, J. L., Murray, G. I., Calogero, R. A., De Bari, C., Zammit, P. S., Delorenzi, M., Wagers, A. J., Shipley, J., Wackerhage, H., & 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

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

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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.",

keywords = "skeletal-muscle, stem-cells, gene-expression, growth-control, self-renewal, differentiation, transcription, pathway, MYOD, quiescent",

author = "Tremblay, {Annie M.} and Edoardo Missiaglia and Galli, {Giorgio G.} and Simone Hettmer and Roby Urcia and Matteo Carrara and Judson, {Robert N.} and Khin Thway and Gema Nadal and Selfe, {Joanna L.} and Murray, {Graeme Ian} and Calogero, {Raffaele A.} and {De Bari}, Cosimo and Zammit, {Peter S.} and Mauro Delorenzi and Wagers, {Amy J.} and Janet Shipley and Henning Wackerhage and Camargo, {Fernando D.}",

note = "We 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{\textquoteright}s and Alex{\textquoteright}s Lemonade Stand Foundation (S.H.). Mouse microarray studies were performed by the Molecular Genetics Core Facility at Children{\textquoteright}s Hospital Boston supported by NIH-P50-NS40828 and NIH-P30-HD18655. The Children{\textquoteright}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{\textquoteright}s Hospital Boston Imaging Core facility.",

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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

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AU - Shipley, Janet

AU - Wackerhage, Henning

AU - Camargo, Fernando D.

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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

SN - 1535-6108

VL - 26

SP - 273

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JO - Cancer Cell

JF - Cancer Cell

IS - 2

ER -

The Hippo Transducer YAP1 Transforms Activated Satellite Cells and Is a Potent Effector of Embryonal Rhabdomyosarcoma Formation

Abstract

Bibliographical note

Keywords

UN SDGs

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Cosimo De Bari

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