Open AccessDIAPH3 governs the cellular transition to the amoeboid tumour phenotype
Author(s) -
Hager Martin H.,
Morley Samantha,
Bielenberg Diane R.,
Gao Sizhen,
Morello Matteo,
Holcomb Ilo.,
Liu Wennuan,
Mouneimne Ghassan,
Demichelis Francesca,
Kim Jayoung,
Solomon Keith R.,
Adam Rosalyn M.,
Isaacs William B.,
Higgs Henry N.,
Vessella Robert L.,
Di Vizio Dolores,
Freeman Michael R.
Publication year - 2012
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.1002/emmm.201200242
Subject(s) - biology , gene silencing , metastasis , cancer research , endocytic cycle , phenotype , clonogenic assay , endosome , regulator , mapk/erk pathway , microbiology and biotechnology , cancer , cell , signal transduction , endocytosis , genetics , gene
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.