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Stathmin mediates neuroblastoma metastasis in a tubulin-independent manner via RhoA/ROCK signaling and enhanced transendothelial migration

Oncogene volume 36, pages 501–511 (2017)Cite this article

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Abstract

Neuroblastoma, the most common solid tumor of young children, frequently presents with aggressive metastatic disease and for these children the 5-year survival rates are dismal. Metastasis, the movement of cancer cells from one site to another, involves remodeling of the cytoskeleton including altered microtubule dynamics. The microtubule-destabilizing protein, stathmin, has recently been shown to mediate neuroblastoma metastasis although precise functions remain poorly defined. In this study we investigated stathmin’s contribution to the metastatic process and potential mechanism(s) by which it exerts these effects. Stathmin suppression significantly reduced neuroblastoma cell invasion of 3D tumor spheroids into an extracellular matrix. Moreover, inhibiting stathmin expression significantly reduced transendothelial migration in two different neuroblastoma cell lines in vitro. Inhibition of ROCK, a key regulator of cell migration, in neuroblastoma cells highlighted that stathmin regulates transendothelial migration through ROCK signaling. Reduced stathmin expression in neuroblastoma cells significantly increased the activation of the RhoA small GTPase. Notably, re-expression of either wild type or a phospho-mimetic stathmin mutant (4E) made defective in tubulin binding returned cell migration and transendothelial migration back to control levels, indicating that stathmin may influence these processes in neuroblastoma cells independent of tubulin binding. Finally, stathmin suppression in neuroblastoma cells significantly reduced whole body, lung, kidney and liver metastases in an experimental metastases mouse model. In conclusion, stathmin suppression interferes with the metastatic process via RhoA/ROCK signaling in neuroblastoma cells. These findings highlight the importance of stathmin to the metastatic process and its potential as a therapeutic target for the treatment of neuroblastoma.

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Acknowledgements

We thank the Children’s Cancer Institute, which is affiliated with the University of New South Wales (UNSW Australia), and Sydney Children’s Hospital Network and by grants from the Cancer Council New South Wales (to MK), Kids Cancer Project (to MK), ARC Future Fellowship (to DCHN; FT120100193), Hope Funds for Cancer Research Fellowship (to FLB; HFCR-14-06-04), Cancer Institute NSW Career Development Fellowship (15/CDF/1-02) and NHMRC Senior Research Fellowships (to MK; APP1058299). MK and TPD are funded by the Australian Research Council Centre of Excellence in Convergent Bio-Nano Science and Technology (project number CE140100036). This research was supported by a Cancer Institute of New South Wales infrastructure award.

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Authors and Affiliations

  1. Tumour Biology and Targeting Program, Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Australia, Sydney, New South Wales, Australia

    C M Fife, S M Sagnella, W S Teo, S T Po'uha, J A McCarroll & M Kavallaris

  2. ARC Centre of Excellence in Convergent Bio-Nano Science and Technology and Australian Centre for NanoMedicine, UNSW Australia, Sydney, New South Wales, Australia

    C M Fife, S M Sagnella, W S Teo, S T Po'uha, J A McCarroll & M Kavallaris

  3. Biotechnology and Biomolecular Sciences, UNSW Australia, Sydney, New South Wales, Australia

    F L Byrne

  4. Department of Biochemistry and Molecular Biology, University of Melbourne, Melbourne, Victoria, Australia

    Y Y C Yeap & D C H Ng

  5. School of Biomedical Science, University of Queensland, Brisbane, Queensland, Australia

    Y Y C Yeap & D C H Ng

  6. ARC Centre for Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Victoria, Australia

    T P Davis

  7. Department of Chemistry University of Warwick, Coventry, UK

    T P Davis

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  1. C M Fife
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Fife, C., Sagnella, S., Teo, W. et al. Stathmin mediates neuroblastoma metastasis in a tubulin-independent manner via RhoA/ROCK signaling and enhanced transendothelial migration. Oncogene 36, 501–511 (2017). https://doi.org/10.1038/onc.2016.220

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