DIAPH3 governs the cellular transition to the amoeboid tumour phenotype

Authors

  • Martin H. Hager,

    1. Urological Diseases Research Center, Children's Hospital Boston, Boston, MA, USA
    2. Department of Surgery, Harvard Medical School, Boston, MA, USA
    3. Present address: R&D Division, Oncology Research Laboratories, Daiichi Sankyo Europe, Munich, Germany
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    • These authors contributed equally to this work.

  • Samantha Morley,

    1. Urological Diseases Research Center, Children's Hospital Boston, Boston, MA, USA
    2. Department of Surgery, Harvard Medical School, Boston, MA, USA
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    • These authors contributed equally to this work.

  • Diane R. Bielenberg,

    1. Department of Surgery, Harvard Medical School, Boston, MA, USA
    2. Vascular Biology Program, Children's Hospital Boston, Boston, MA, USA
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  • Sizhen Gao,

    1. Department of Cell Biology, Harvard Medical School, Boston, MA, USA
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  • Matteo Morello,

    1. Urological Diseases Research Center, Children's Hospital Boston, Boston, MA, USA
    2. Department of Surgery, Harvard Medical School, Boston, MA, USA
    3. Division of Cancer Biology and Therapeutics, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
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  • Ilona N. Holcomb,

    1. Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA
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  • Wennuan Liu,

    1. Center for Cancer Genomics, Wake Forest University, Winston-Salem, NC, USA
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  • Ghassan Mouneimne,

    1. Department of Cell Biology, Harvard Medical School, Boston, MA, USA
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  • Francesca Demichelis,

    1. Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA
    2. Centre for Integrative Biology, University of Trento, Trento, Italy
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  • Jayoung Kim,

    1. Urological Diseases Research Center, Children's Hospital Boston, Boston, MA, USA
    2. Department of Surgery, Harvard Medical School, Boston, MA, USA
    3. Division of Cancer Biology and Therapeutics, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
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  • Keith R. Solomon,

    1. Urological Diseases Research Center, Children's Hospital Boston, Boston, MA, USA
    2. Department of Orthopaedic Surgery, Children's Hospital Boston, Harvard Medical School, Boston, MA, USA
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  • Rosalyn M. Adam,

    1. Urological Diseases Research Center, Children's Hospital Boston, Boston, MA, USA
    2. Department of Surgery, Harvard Medical School, Boston, MA, USA
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  • William B. Isaacs,

    1. Department of Urology and Oncology, Johns Hopkins School of Medicine, Baltimore, MD, USA
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  • Henry N. Higgs,

    1. Department of Biochemistry, Dartmouth Medical School, Hanover, NH, USA
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  • Robert L. Vessella,

    1. Department of Urology, University of Washington, Seattle, WA, USA
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  • Dolores Di Vizio,

    1. Urological Diseases Research Center, Children's Hospital Boston, Boston, MA, USA
    2. Department of Surgery, Harvard Medical School, Boston, MA, USA
    3. Division of Cancer Biology and Therapeutics, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
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  • Michael R. Freeman

    Corresponding author
    1. Urological Diseases Research Center, Children's Hospital Boston, Boston, MA, USA
    2. Department of Surgery, Harvard Medical School, Boston, MA, USA
    3. Division of Cancer Biology and Therapeutics, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
    4. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA
    • Tel: +1 310 423 7069; Fax: +1 310 423 0139

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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.

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