Poster Presentation 14th International Biennial Conference on Metastasis Research 2012

The Embryonic Morphogen Nodal Promotes EMT, Invasion and Metastasis via a Non-Canonical ERK-Dependent Pathway (#119)

Daniela F Quail 1 , Guihua Zhang 1 , David A Hess 1 , Lynne-Marie Postovit 1
  1. Western University, London, ON, Canada

Breast cancer progression from a localized lesion to an invasive metastatic disease is characterized by alterations in cellular migration, and epithelial-to-mesenchymal transition (EMT). Studies have shown that this transition is associated with an up-regulation 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 plays a specialized role in adult life during placentation, and an aberrant role during cancer progression. Here, we show that Nodal over-expression in poorly invasive breast cancer and choriocarcinoma cell lines causes increased invasion and migration in vitro concomitant with the induction of EMT-associated phenomena. We show that Nodal promotes these invasive events via an Extracellular Regulated Kinase (ERK) dependent pathway. Since Nodal normally signals through SMADs, these findings lend insight into alternative pathways that are hijacked by this protein in cancer. To evaluate the clinical implications of our results for cancer, 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 reduces invasion and causes a Mesenchymal-to-Epithelial-like Transition (MET) concomitant with a mitigation of ERK activation. 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 metastatic disease.