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DIAPH3 governs the cellular transition to the amoeboid tumour phenotype

Martin H. Hager, Samantha Morley, Diane R. Bielenberg, Sizhen Gao, Matteo Morello, Ilona N. Holcomb, Wennuan Liu, Ghassan Mouneimne, Francesca Demichelis, Jayoung Kim, Keith R. Solomon, Rosalyn M. Adam, William B. Isaacs, Henry N. Higgs, Robert L. Vessella, Dolores Di Vizio, Michael R. Freeman

Author Affiliations

  1. Martin H. Hager1,2,15,,
  2. Samantha Morley1,2,,
  3. Diane R. Bielenberg2,3,
  4. Sizhen Gao4,
  5. Matteo Morello1,2,5,
  6. Ilona N. Holcomb6,
  7. Wennuan Liu7,
  8. Ghassan Mouneimne4,
  9. Francesca Demichelis8,9,
  10. Jayoung Kim1,2,5,
  11. Keith R. Solomon1,10,
  12. Rosalyn M. Adam1,2,
  13. William B. Isaacs11,
  14. Henry N. Higgs12,
  15. Robert L. Vessella13,
  16. Dolores Di Vizio1,2,5 and
  17. Michael R. Freeman (michael.freeman{at}cshs.org) *,1,2,5,14
  1. 1Urological Diseases Research Center, Children's Hospital Boston, Boston, MA, USA
  2. 2Department of Surgery, Harvard Medical School, Boston, MA, USA
  3. 3Vascular Biology Program, Children's Hospital Boston, Boston, MA, USA
  4. 4Department of Cell Biology, Harvard Medical School, Boston, MA, USA
  5. 5Division of Cancer Biology and Therapeutics, Samuel Oschin Comprehensive Cancer Institute, Cedars‐Sinai Medical Center, Los Angeles, CA, USA
  6. 6Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA
  7. 7Center for Cancer Genomics, Wake Forest University, Winston‐Salem, NC, USA
  8. 8Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA
  9. 9Centre for Integrative Biology, University of Trento, Trento, Italy
  10. 10Department of Orthopaedic Surgery, Children's Hospital Boston, Harvard Medical School, Boston, MA, USA
  11. 11Department of Urology and Oncology, Johns Hopkins School of Medicine, Baltimore, MD, USA
  12. 12Department of Biochemistry, Dartmouth Medical School, Hanover, NH, USA
  13. 13Department of Urology, University of Washington, Seattle, WA, USA
  14. 14Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA
  15. 15Present address: R&D Division, Oncology Research Laboratories, Daiichi Sankyo Europe, Munich, Germany
  1. *Tel: +1 310 423 7069; Fax: +1 310 423 0139
  1. These authors contributed equally to this work.

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Abstract

Therapies for most malignancies are generally ineffective once metastasis occurs. While tumour cells migrate through tissues using diverse strategies, the signalling networks controlling such behaviours in human tumours are poorly understood. Here we define a role for the Diaphanous‐related formin‐3 (DIAPH3) as a non‐canonical regulator of metastasis that restrains conversion to amoeboid cell behaviour in multiple cancer types. The DIAPH3 locus is close to RB1, within a narrow consensus region of deletion on chromosome 13q in prostate, breast and hepatocellular carcinomas. DIAPH3 silencing in human carcinoma cells destabilized microtubules and induced defective endocytic trafficking, endosomal accumulation of EGFR, and hyperactivation of EGFR/MEK/ERK signalling. Silencing also evoked amoeboid properties, increased invasion and promoted metastasis in mice. In human tumours, DIAPH3 down‐regulation was associated with aggressive or metastatic disease. DIAPH3‐silenced cells were sensitive to MEK inhibition, but showed reduced sensitivity to EGFR inhibition. These findings have implications for understanding mechanisms of metastasis, and suggest that identifying patients with chromosomal deletions at DIAPH3 may have prognostic value.

  • Received November 23, 2011.
  • Revision received March 19, 2012.
  • Accepted March 28, 2012.

This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

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