4.8 Article

Dystrophin is a tumor suppressor in human cancers with myogenic programs

Journal

NATURE GENETICS
Volume 46, Issue 6, Pages 601-606

Publisher

NATURE PUBLISHING GROUP
DOI: 10.1038/ng.2974

Keywords

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Funding

  1. US National Institutes of Health [1P50CA127003-07, 1P50CA168512-01, 5R01DK058185-12]
  2. Virginia and Daniel K. Ludwig Trust
  3. GIST Cancer Research Fund
  4. Life Raft Group
  5. Cesarini Pan-Mass Challenge for GIST
  6. Paul's Posse of the Pan-Mass Challenge
  7. Bernard F. and Alva B. Gimbel Foundation
  8. Sarcoma Alliance for Research Through Collaboration
  9. Erica Kaitz LMS Research NOW Fund

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Many common human mesenchymal tumors, including gastrointestinal stromal tumor (GIST), rhabdomyosarcoma (RMS) and leiomyosarcoma (LMS), feature myogenic differentiation(1-3). 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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