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Tyrosine phosphatase SHP2 increases cell motility in triple-negative breast cancer through the activation of SRC-family kinases

Oncogene volume 34, pages 2272–2278 (2015)Cite this article

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Abstract

Tumor cell migration has a fundamental role in early steps of metastasis, the fatal hallmark of cancer. In the present study, we investigated the effects of the tyrosine phosphatase, SRC-homology 2 domain-containing phosphatase 2 (SHP2), on cell migration in metastatic triple-negative breast cancer (TNBC), an aggressive disease associated with a poor prognosis for which a targeted therapy is not yet available. Using mouse models and multiphoton intravital imaging, we have identified a crucial effect of SHP2 on TNBC cell motility in vivo. Further, analysis of TNBC cells revealed that SHP2 also influences cell migration, chemotaxis and invasion in vitro. Unbiased phosphoproteomics and biochemical analysis showed that SHP2 activates several SRC-family kinases and downstream targets, most of which are inducers of migration and invasion. In particular, direct interaction between SHP2 and c-SRC was revealed by a fluorescence resonance energy transfer assay. These results suggest that SHP2 is a crucial factor during early steps of TNBC migration to distant organs.

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Acknowledgements

We thank C Kuperwasser for the SUM159 cells and S Gambhir for the pFU-Luc2-eGFP construct, L Bonapace for technical assistance with the intravital microscope, L Gelman for help with the FRET experiments, S Bourke and M Kirschmann for help with image acquisition and analysis, and I Klebba and H Brinkhaus for technical assistance. M-MC is supported by a FP7 Marie-Curie Fellowship and NA is a fellow of the Swiss National Science Foundation and the Human Frontiers Science Program. Research in the laboratory of MB-A is supported by the Novartis Research Foundation, the European Research Council (ERC starting grant 243211-PTPsBDC), the Swiss Cancer League and the Krebsliga Beider Basel.

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Author notes

  1. N Sausgruber and M-M Coissieux: These authors contributed equally to this work.

Authors and Affiliations

  1. Mechanisms of cancer, Friedrich Miescher Institute (FMI) for Biomedical Research, Basel, Switzerland

    N Sausgruber, M-M Coissieux, A Britschgi, J Wyckoff, N Aceto, C Leroy, M B Stadler & M Bentires-Alj

  2. Koch Institute for Integrated Cancer Research, Massachusetts Institute for Technology, Cambridge, MA, USA,

    J Wyckoff

  3. Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA,

    N Aceto

  4. Analytical sciences and Imaging, Novartis Institutes for Biomedical Research, Basel, Switzerland

    C Leroy, H Voshol & D Bonenfant

  5. Swiss Institute of Bioinformatics, Basel, Switzerland

    M B Stadler

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  1. N Sausgruber
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Correspondence to M Bentires-Alj.

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Sausgruber, N., Coissieux, MM., Britschgi, A. et al. Tyrosine phosphatase SHP2 increases cell motility in triple-negative breast cancer through the activation of SRC-family kinases. Oncogene 34, 2272–2278 (2015). https://doi.org/10.1038/onc.2014.170

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