TY - JOUR
T1 - Dystrophin is a tumor suppressor in human cancers with myogenic programs
AU - Wang, Yuexiang
AU - Marino-Enriquez, Adrian
AU - Bennett, Richard R.
AU - Zhu, Meijun
AU - Shen, Yiping
AU - Eilers, Grant
AU - Lee, Jen Chieh
AU - Henze, Joern
AU - Fletcher, Benjamin S.
AU - Gu, Zhizhan
AU - Fox, Edward A.
AU - Antonescu, Cristina R.
AU - Fletcher, Christopher D.M.
AU - Guo, Xiangqian
AU - Raut, Chandrajit P.
AU - Demetri, George D.
AU - Van De Rijn, Matt
AU - Ordog, Tamas
AU - Kunkel, Louis M.
AU - Fletcher, Jonathan A.
N1 - Funding Information:
We thank J. Tremblay (Quebec University Hospital) for the pCR3.1-miniDMD construct; T. Taguchi (Kochi Medical School) for the GIST-T1 cell line; Y. Hayashi, M. Bardsley and H. Qiu for their expert technical assistance; and S. Bauer (West German Cancer Center) for useful discussions and for funding support of J.H. This work was supported by grants from the US National Institutes of Health, including 1P50CA127003-07 (J.A.F. and G.D.D.), 1P50CA168512-01 (J.A.F., G.D.D. and A.M.-E.) and 5R01DK058185-12 (T.O.), and by the Virginia and Daniel K. Ludwig Trust for Cancer Research (J.A.F. and G.D.D.), the GIST Cancer Research Fund (J.A.F.), the Life Raft Group (J.A.F., T.O. and M.v.d.R.), the Cesarini Pan-Mass Challenge for GIST (J.A.F. and G.D.D.), Paul’s Posse of the Pan-Mass Challenge (J.A.F. and G.D.D.), the Bernard F. and Alva B. Gimbel Foundation (L.M.K.), the Sarcoma Alliance for Research Through Collaboration (A.M.-E.) and the Erica Kaitz LMS Research NOW Fund (J.A.F., A.M.-E. and G.D.D.).
PY - 2014/6
Y1 - 2014/6
N2 - 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.
AB - 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.
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U2 - 10.1038/ng.2974
DO - 10.1038/ng.2974
M3 - Article
C2 - 24793134
AN - SCOPUS:84901680208
SN - 1061-4036
VL - 46
SP - 601
EP - 606
JO - Nature Genetics
JF - Nature Genetics
IS - 6
ER -
