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

Research output: Contribution to journalArticle

46 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)743-760
Number of pages18
JournalEMBO Molecular Medicine
Volume4
Issue number8
DOIs
StatePublished - Aug 2012
Externally publishedYes

Fingerprint

Phenotype
Neoplasm Metastasis
Mitogen-Activated Protein Kinase Kinases
Neoplasms
Microtubules
Prostate
Hepatocellular Carcinoma
Consensus
Down-Regulation
Breast Neoplasms
Carcinoma
Inhibition (Psychology)
Therapeutics

Keywords

  • Cytoskeleton
  • EGFR
  • Endocytosis
  • Mesenchymal-to-amoeboid transition
  • Metastasis

ASJC Scopus subject areas

  • Molecular Medicine

Cite this

Hager, M. H., Morley, S., Bielenberg, D. R., Gao, S., Morello, M., Holcomb, I. N., ... Freeman, M. R. (2012). DIAPH3 governs the cellular transition to the amoeboid tumour phenotype. EMBO Molecular Medicine, 4(8), 743-760. https://doi.org/10.1002/emmm.201200242

DIAPH3 governs the cellular transition to the amoeboid tumour phenotype. / Hager, Martin H.; Morley, Samantha; Bielenberg, Diane R.; Gao, Sizhen; Morello, Matteo; Holcomb, Ilona N.; 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.

In: EMBO Molecular Medicine, Vol. 4, No. 8, 08.2012, p. 743-760.

Research output: Contribution to journalArticle

Hager, MH, Morley, S, Bielenberg, DR, Gao, S, Morello, M, Holcomb, IN, Liu, W, Mouneimne, G, Demichelis, F, Kim, J, Solomon, KR, Adam, RM, Isaacs, WB, Higgs, HN, Vessella, RL, Di Vizio, D & Freeman, MR 2012, 'DIAPH3 governs the cellular transition to the amoeboid tumour phenotype', EMBO Molecular Medicine, vol. 4, no. 8, pp. 743-760. https://doi.org/10.1002/emmm.201200242
Hager MH, Morley S, Bielenberg DR, Gao S, Morello M, Holcomb IN et al. DIAPH3 governs the cellular transition to the amoeboid tumour phenotype. EMBO Molecular Medicine. 2012 Aug;4(8):743-760. https://doi.org/10.1002/emmm.201200242
Hager, Martin H. ; Morley, Samantha ; Bielenberg, Diane R. ; Gao, Sizhen ; Morello, Matteo ; Holcomb, Ilona N. ; 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. / DIAPH3 governs the cellular transition to the amoeboid tumour phenotype. In: EMBO Molecular Medicine. 2012 ; Vol. 4, No. 8. pp. 743-760.
@article{8cc17df316a644be8fa0ca139c0ae5e9,
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.",
keywords = "Cytoskeleton, EGFR, Endocytosis, Mesenchymal-to-amoeboid transition, Metastasis",
author = "Hager, {Martin H.} and Samantha Morley and Bielenberg, {Diane R.} and Sizhen Gao and Matteo Morello and Holcomb, {Ilona N.} and Wennuan Liu and Ghassan Mouneimne and Francesca Demichelis and Jayoung Kim and Solomon, {Keith R.} and Adam, {Rosalyn M.} and Isaacs, {William B.} and Higgs, {Henry N.} and Vessella, {Robert L.} and {Di Vizio}, Dolores and Freeman, {Michael R.}",
year = "2012",
month = "8",
doi = "10.1002/emmm.201200242",
language = "English (US)",
volume = "4",
pages = "743--760",
journal = "EMBO Molecular Medicine",
issn = "1757-4676",
publisher = "Wiley-Blackwell",
number = "8",

}

TY - JOUR

T1 - DIAPH3 governs the cellular transition to the amoeboid tumour phenotype

AU - Hager, Martin H.

AU - Morley, Samantha

AU - Bielenberg, Diane R.

AU - Gao, Sizhen

AU - Morello, Matteo

AU - Holcomb, Ilona N.

AU - Liu, Wennuan

AU - Mouneimne, Ghassan

AU - Demichelis, Francesca

AU - Kim, Jayoung

AU - Solomon, Keith R.

AU - Adam, Rosalyn M.

AU - Isaacs, William B.

AU - Higgs, Henry N.

AU - Vessella, Robert L.

AU - Di Vizio, Dolores

AU - Freeman, Michael R.

PY - 2012/8

Y1 - 2012/8

N2 - 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.

AB - 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.

KW - Cytoskeleton

KW - EGFR

KW - Endocytosis

KW - Mesenchymal-to-amoeboid transition

KW - Metastasis

UR - http://www.scopus.com/inward/record.url?scp=84864823696&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84864823696&partnerID=8YFLogxK

U2 - 10.1002/emmm.201200242

DO - 10.1002/emmm.201200242

M3 - Article

C2 - 22593025

AN - SCOPUS:84864823696

VL - 4

SP - 743

EP - 760

JO - EMBO Molecular Medicine

JF - EMBO Molecular Medicine

SN - 1757-4676

IS - 8

ER -