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Targeting Lyn regulates Snail family shuttling and inhibits metastasis

Oncogene volume 36, pages 3964–3975 (2017)Cite this article

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Abstract

The acquisition of an invasive phenotype by epithelial cells occurs through a loss of cellular adhesion and polarity, heralding a multistep process that leads to metastatic dissemination. Since its characterization in 1995, epithelial–mesenchymal transition (EMT) has been closely linked to the metastatic process. As a defining aspect of EMT, loss of cell adhesion through downregulation of E-cadherin is carried out by several transcriptional repressors; key among them the SNAI family of transcription factors. Here we identify for the first time that Lyn kinase functions as a key modulator of SNAI family protein localization and stability through control of the Vav-Rac1-PAK1 (Vav-Rac1-p21-activated kinase) pathway. Accordingly, targeting Lyn in vitro reduces EMT and in vivo reduces metastasis of primary tumors. We also demonstrate the clinical relevance of targeting Lyn as a key player controlling EMT; patient samples across many cancers revealed a strong negative correlation between Lyn and E-cadherin, and high Lyn expression in metastatic tumors as well as metastasis-prone primary tumors. This work reveals a novel pancancer mechanism of Lyn-dependent control of EMT and further underscores the role of this kinase in tumor progression.

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Acknowledgements

This work was supported by the Terry Fox Research Institute, Michael Smith Foundation, Prostate Cancer Canada and Canadian Institutes of Health Research. We would like to thank Dr Peter Black for the UC13 and UC13-luciferase cells, and Dr Yuzhou Wang for Oncomine access. We also appreciate the assistance of Eliana Beraldi and Shannon Awery for experimental support.

Author contributions

Conceptualization, design and interpretation of data: DT, SV, JLB and AZ; writing—original draft: DT; writing—review and editing, JLB, SV and AZ; in vitro data acquisition: DT, SV and KN; in silico data acquisition: DT; in vivo data acquisition (mouse): DT, SF and IM; in vivo data acquisition (zebrafish): DT, XS and CG-E; mice tissue: MER and KWH; funding acquisition and supervision: AZ.

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Authors and Affiliations

  1. Department of Urology, Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada

    D Thaper, S Vahid, K M Nip, I Moskalev, S Frees, K Ketola, J L Bishop & A Zoubeidi

  2. Department of Urologic Science, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada

    D Thaper, S Vahid, K M Nip & A Zoubeidi

  3. Department Ophthalmology and Visual Sciences, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada

    X Shan & C Gregory-Evans

  4. Department of Microbiology and Immunology, Faculty of Science, University of British Columbia, Vancouver, BC, Canada

    M E Roberts & K W Harder

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Thaper, D., Vahid, S., Nip, K. et al. Targeting Lyn regulates Snail family shuttling and inhibits metastasis. Oncogene 36, 3964–3975 (2017). https://doi.org/10.1038/onc.2017.5

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