DIAPH3 governs the cellular transition to the amoeboid tumour phenotype

EMBO Molecular Medicine

Martin H. Hager⁹  Samantha Morley⁹  Diane R. Bielenberg¹  Sizhen Gao⁷  Matteo Morello⁹  Ilona N. Holcomb⁸  Wennuan Liu⁵  Ghassan Mouneimne⁷  Francesca Demichelis³  Jayoung Kim⁹  Keith R. Solomon⁹  Rosalyn M. Adam⁹  William B. Isaacs⁶  Henry N. Higgs²  Robert L. Vessella⁴  Dolores Di Vizio⁹ 

[1] Department of Surgery, Harvard Medical School, Boston, MA, USA;Department of Biochemistry, Dartmouth Medical School, Hanover, NH, USA;Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA;Department of Urology, University of Washington, Seattle, WA, USA;Center for Cancer Genomics, Wake Forest University, Winston-Salem, NC, USA;Department of Urology and Oncology, Johns Hopkins School of Medicine, Baltimore, MD, USA;Department of Cell Biology, Harvard Medical School, Boston, MA, USA;Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA;Urological Diseases Research Center, Children's Hospital Boston, Boston, MA, USA

关键词: cytoskeleton;    EGFR;    endocytosis;    mesenchymal‐to‐amoeboid transition;    metastasis;   

DOI  :  10.1002/emmm.201200242

来源: Wiley

【 摘 要 】

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.

【 授权许可】

CC BY   
Copyright © 2012 EMBO Molecular Medicine

Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.