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Role of the YAP Oncoprotein in Priming Ras-Driven Rhabdomyosarcoma.

Publication ,  Journal Article
Slemmons, KK; Crose, LES; Rudzinski, E; Bentley, RC; Linardic, CM
Published in: PLoS One
2015

Rhabdomyosarcoma (RMS), a cancer characterized by features of skeletal muscle histogenesis, is the most common soft tissue sarcoma of childhood and adolescence. Survival for high-risk groups is less than 30% at 5 years. RMS also occurs during adulthood, with a lower incidence but higher mortality. Recently, mutational profiling has revealed a correlation between activating Ras mutations in the embryonal (eRMS) and pleomorphic (pRMS) histologic variants of RMS, and a poorer outcome for those patients. Independently, the YAP transcriptional coactivator, an oncoprotein kept in check by the Hippo tumor suppressor pathway, is upregulated in eRMS. Here we show that YAP promotes cell proliferation and antagonizes apoptosis and myogenic differentiation of human RMS cells bearing oncogenic Ras mutations in cell culture studies in vitro and in murine xenografts in vivo. Pharmacologic inhibition of YAP by the benzoporphyrin derivative verteporfin decreased cell proliferation and tumor growth in vivo. To interrogate the temporal contribution of YAP in eRMS tumorigenesis, we used a primary human cell-based genetic model of Ras-driven RMS. Constitutively active YAP functioned as an early genetic lesion, permitting bypass of senescence and priming myoblasts to tolerate subsequent expression of hTERT and oncogenic Ras, which were necessary and sufficient to generate murine xenograft tumors mimicking RMS in vivo. This work provides evidence for cooperation between YAP and oncogenic Ras in RMS tumorigenesis, laying the foundation for preclinical co-targeting of these pathways.

Duke Scholars

Published In

PLoS One

DOI

EISSN

1932-6203

Publication Date

2015

Volume

10

Issue

10

Start / End Page

e0140781

Location

United States

Related Subject Headings

  • ras Proteins
  • YAP-Signaling Proteins
  • Telomerase
  • Rhabdomyosarcoma
  • Real-Time Polymerase Chain Reaction
  • Phosphoproteins
  • Mice, SCID
  • Mice
  • Immunohistochemistry
  • Immunoblotting
 

Citation

APA
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ICMJE
MLA
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Slemmons, K. K., Crose, L. E. S., Rudzinski, E., Bentley, R. C., & Linardic, C. M. (2015). Role of the YAP Oncoprotein in Priming Ras-Driven Rhabdomyosarcoma. PLoS One, 10(10), e0140781. https://doi.org/10.1371/journal.pone.0140781
Slemmons, Katherine K., Lisa E. S. Crose, Erin Rudzinski, Rex C. Bentley, and Corinne M. Linardic. “Role of the YAP Oncoprotein in Priming Ras-Driven Rhabdomyosarcoma.PLoS One 10, no. 10 (2015): e0140781. https://doi.org/10.1371/journal.pone.0140781.
Slemmons KK, Crose LES, Rudzinski E, Bentley RC, Linardic CM. Role of the YAP Oncoprotein in Priming Ras-Driven Rhabdomyosarcoma. PLoS One. 2015;10(10):e0140781.
Slemmons, Katherine K., et al. “Role of the YAP Oncoprotein in Priming Ras-Driven Rhabdomyosarcoma.PLoS One, vol. 10, no. 10, 2015, p. e0140781. Pubmed, doi:10.1371/journal.pone.0140781.
Slemmons KK, Crose LES, Rudzinski E, Bentley RC, Linardic CM. Role of the YAP Oncoprotein in Priming Ras-Driven Rhabdomyosarcoma. PLoS One. 2015;10(10):e0140781.

Published In

PLoS One

DOI

EISSN

1932-6203

Publication Date

2015

Volume

10

Issue

10

Start / End Page

e0140781

Location

United States

Related Subject Headings

  • ras Proteins
  • YAP-Signaling Proteins
  • Telomerase
  • Rhabdomyosarcoma
  • Real-Time Polymerase Chain Reaction
  • Phosphoproteins
  • Mice, SCID
  • Mice
  • Immunohistochemistry
  • Immunoblotting