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Nodal promotes invasive phenotypes via a mitogen-activated protein kinase-dependent pathway

Oncogene volume 33, pages 461–473 (2014)Cite this article

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Abstract

The progression of cancer from localized to invasive disease is requisite for metastasis, and is often characterized by epithelial-to-mesenchymal transition (EMT) and alterations in cellular adhesion and migration. Studies have shown that this transition is associated with an upregulation of embryonic stem cell-associated genes, resulting in a dedifferentiated phenotype and poor patient prognosis. Nodal is an embryonic factor that plays a critical role in promoting early invasive events during development. Nodal is silenced as stem cells differentiate; however, it re-emerges in adult life during placentation and mammary gland development, and is aberrantly expressed in many cancers. Here, we show that Nodal overexpression, in poorly invasive breast cancer and choriocarcinoma cells, causes increased invasion and migration in vitro. Furthermore, we show that Nodal overexpression in these epithelial cancer types induces an EMT-like event concomitant with the internalization of E-Cadherin. This ability of Nodal to promote cellular invasion and EMT-like phenomena is dependent upon the phosphorylation of ERK1/2. As Nodal normally signals through SMADs, these findings lend insight into an alternative pathway that is hijacked by this protein in cancer. To evaluate the clinical implications of our results, we show that Nodal inhibition reduces liver tumor burden in a model of spontaneous breast cancer metastasis in vivo, and that Nodal loss-of-function in aggressive breast cancer lines results in a decrease in invasive phenotypes. Our results demonstrate that Nodal is involved in promoting invasion in multiple cellular contexts, and that Nodal inhibition may be useful as a therapeutic target for patients with progressive disease.

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Acknowledgements

We thank LA Walsh and SD Findlay for making the Nodal expression construct, and M Jewer and A Cloutier-Bosworth for assisting with tissue scoring. This work was supported by the Canadian Institutes for Health Research (MOP 89714, MOP 119589 and PLS 95381) and the Cancer Research Society to LMP. DQ is supported by fellowships from the Canadian Breast Cancer Foundation, and a CIHR training grant. LMP is the recipient of the Premier New Investigator Award from the CIHR. DAH is the recipient of a new investigator award and MacDonald Scholarship for the Canadian Heart and Stroke Foundation.

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Authors and Affiliations

  1. Department of Anatomy and Cell Biology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, ON, Canada

    D F Quail, G Zhang, S D Findlay & L-M Postovit

  2. Department of Physiology and Pharmacology, University of Western Ontario, London, ON, Canada

    D A Hess

  3. Robarts Research Institute, University of Western Ontario, London, ON, Canada

    G Zhang, S D Findlay, D A Hess & L-M Postovit

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  1. D F Quail
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Correspondence to L-M Postovit.

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LMP holds a patent regarding targeting Nodal in cancer. The remaining authors declare no conflict of interest.

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Quail, D., Zhang, G., Findlay, S. et al. Nodal promotes invasive phenotypes via a mitogen-activated protein kinase-dependent pathway. Oncogene 33, 461–473 (2014). https://doi.org/10.1038/onc.2012.608

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