Targeting Lyn regulates Snail family shuttling and inhibits metastasis.

D Thaper, S Vahid, K M Nip, I Moskalev, X Shan, S Frees, M E Roberts, K Ketola, K W Harder, C Gregory-Evans, J L Bishop, A Zoubeidi

Oncogene 2017 Jul 13

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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.

Citation

D Thaper, S Vahid, K M Nip, I Moskalev, X Shan, S Frees, M E Roberts, K Ketola, K W Harder, C Gregory-Evans, J L Bishop, A Zoubeidi. Targeting Lyn regulates Snail family shuttling and inhibits metastasis. Oncogene. 2017 Jul 13;36(28):3964-3975