title: DIAPH3 governs the cellular transition to the amoeboid tumour phenotype.
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.
authors.affiliation: Urological Diseases Research Center, Children's Hospital Boston, Boston, MA, USA.
authors.forename: Martin H
authors.initials: MH
authors.lastname: Hager
authors.forename: Samantha
authors.initials: S
authors.lastname: Morley
authors.forename: Diane R
authors.initials: DR
authors.lastname: Bielenberg
authors.forename: Sizhen
authors.initials: S
authors.lastname: Gao
authors.forename: Matteo
authors.initials: M
authors.lastname: Morello
authors.forename: Ilona N
authors.initials: IN
authors.lastname: Holcomb
authors.forename: Wennuan
authors.initials: W
authors.lastname: Liu
authors.forename: Ghassan
authors.initials: G
authors.lastname: Mouneimne
authors.forename: Francesca
authors.initials: F
authors.lastname: Demichelis
authors.forename: Jayoung
authors.initials: J
authors.lastname: Kim
authors.forename: Keith R
authors.initials: KR
authors.lastname: Solomon
authors.forename: Rosalyn M
authors.initials: RM
authors.lastname: Adam
authors.forename: William B
authors.initials: WB
authors.lastname: Isaacs
authors.forename: Henry N
authors.initials: HN
authors.lastname: Higgs
authors.forename: Robert L
authors.initials: RL
authors.lastname: Vessella
authors.forename: Dolores
authors.initials: D
authors.lastname: Di Vizio
authors.forename: Michael R
authors.initials: MR
authors.lastname: Freeman
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D000080865:Formins; D020868:Gene Silencing; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis / Q000473:pathology*; D009369:Neoplasms / Q000473:pathology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C484571:DIAPH3 protein, human; D000080865:Formins