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Molecular and Cellular Biology, July 2009, p. 3722-3737, Vol. 29, No. 13
0270-7306/09/$08.00+0     doi:10.1128/MCB.01164-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

A Twist-Snail Axis Critical for TrkB-Induced Epithelial-Mesenchymal Transition-Like Transformation, Anoikis Resistance, and Metastasis{triangledown} ,§

Marjon A. Smit,1,{dagger} Thomas R. Geiger,1,{dagger} Ji-Ying Song,2 Inna Gitelman,3 and Daniel S. Peeper1*

Division of Molecular Genetics,1 Department of Experimental Animal Pathology, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands,2 Department of Developmental Molecular Genetics, Faculty of Medicine, Ben Gurion University of the Negev, Beer Sheva, 84105, Israel3

Received 23 July 2008/ Returned for modification 26 August 2008/ Accepted 27 April 2009

In a genomewide anoikis suppression screen for metastasis genes, we previously identified the neurotrophic receptor tyrosine kinase TrkB. In mouse xenografts, activated TrkB caused highly invasive and metastatic tumors. Here, we describe that TrkB also induces a strong morphological transformation, resembling epithelial-mesenchymal transition (EMT). This required TrkB kinase activity, a functional mitogen-activated protein kinase pathway, suppression of E-cadherin, and induction of Twist, a transcription factor contributing to EMT and metastasis. RNA interference (RNAi)-mediated Twist depletion blocked TrkB-induced EMT-like transformation, anoikis suppression, and growth of tumor xenografts. By searching for essential effectors of TrkB-Twist signaling, we found that Twist induces Snail, another EMT regulator associated with poor cancer prognosis. Snail depletion impaired EMT-like transformation and anoikis suppression induced by TrkB, but in contrast to Twist depletion, it failed to inhibit tumor growth. Instead, Snail RNAi specifically impaired the formation of lung metastases. Epistasis experiments suggested that Twist acts upstream from Snail. Our results demonstrate that TrkB signaling activates a Twist-Snail axis that is critically involved in EMT-like transformation, tumorigenesis, and metastasis. Moreover, our data shed more light on the epistatic relationship between Twist and Snail, two key transcriptional regulators of EMT and metastasis.

* Corresponding author. Mailing address: Division of Molecular Genetics, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands. Phone: 31205122002. Fax: 31205122011. E-mail: d.peeper{at}nki.nl

{triangledown} Published ahead of print on 4 May 2009.

§ Supplemental material for this article may be found at http://mcb.asm.org/.

{dagger} These authors contributed equally to this work.

Molecular and Cellular Biology, July 2009, p. 3722-3737, Vol. 29, No. 13
0270-7306/09/$08.00+0     doi:10.1128/MCB.01164-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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