Dystrophin is a tumor suppressor in human cancers with myogenic programs

Yuexiang Wang, Adrian Marino-Enriquez, Richard R. Bennett, Meijun Zhu, Yiping Shen, Grant Eilers, Jen Chieh Lee, Joern Henze, Benjamin S. Fletcher, Zhizhan Gu, Edward A. Fox, Cristina R. Antonescu, Christopher D.M. Fletcher, Xiangqian Guo, Chandrajit P. Raut, George D. Demetri, Matt Van De Rijn, Tamas Ordog, Louis M. Kunkel, Jonathan A. Fletcher

Research output: Contribution to journalArticle

71 Scopus citations

Abstract

Many common human mesenchymal tumors, including gastrointestinal stromal tumor (GIST), rhabdomyosarcoma (RMS) and leiomyosarcoma (LMS), feature myogenic differentiation. Here we report that intragenic deletion of the dystrophin-encoding and muscular dystrophy-associated DMD gene is a frequent mechanism by which myogenic tumors progress to high-grade, lethal sarcomas. Dystrophin is expressed in the non-neoplastic and benign counterparts of GIST, RMS and LMS tumors, and DMD deletions inactivate larger dystrophin isoforms, including 427-kDa dystrophin, while preserving the expression of an essential 71-kDa isoform. Dystrophin inhibits myogenic sarcoma cell migration, invasion, anchorage independence and invadopodia formation, and dystrophin inactivation was found in 96%, 100% and 62% of metastatic GIST, embryonal RMS and LMS samples, respectively. These findings validate dystrophin as a tumor suppressor and likely anti-metastatic factor, suggesting that therapies in development for muscular dystrophies may also have relevance in the treatment of cancer.

Original languageEnglish (US)
Pages (from-to)601-606
Number of pages6
JournalNature Genetics
Volume46
Issue number6
DOIs
StatePublished - Jun 2014

ASJC Scopus subject areas

  • Genetics

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    Wang, Y., Marino-Enriquez, A., Bennett, R. R., Zhu, M., Shen, Y., Eilers, G., Lee, J. C., Henze, J., Fletcher, B. S., Gu, Z., Fox, E. A., Antonescu, C. R., Fletcher, C. D. M., Guo, X., Raut, C. P., Demetri, G. D., Van De Rijn, M., Ordog, T., Kunkel, L. M., & Fletcher, J. A. (2014). Dystrophin is a tumor suppressor in human cancers with myogenic programs. Nature Genetics, 46(6), 601-606. https://doi.org/10.1038/ng.2974