Nck deficiency is associated with delayed breast carcinoma progression and reduced metastasis

• DOI: 10.1091/mbc.e17-02-0106
• Publication Date: 2017-09-28T00:50:17Z
• Authors: David C. Morris; Julia L. Popp; Leung K. Tang; Holly C. Gibbs; Emily Schmitt; Sankar P. Chaki; Briana C. Bywaters; Alvin T. Yeh; Weston W. Porter; Robert C. Burghardt; Rola Barhoumi; Gonzalo M. Rivera
• Keywords: Invadopodia; CDC42

Although it is known that noncatalytic region of tyrosine kinase (Nck) regulates cell adhesion and migration by bridging phosphorylation with cytoskeletal remodeling, the role Nck in tumorigenesis metastasis has remained undetermined. Here we report required for growth vascularization primary tumors lung metastases a breast cancer xenograft model as well extravasation following injection carcinoma cells into tail vein. We provide evidence directs polarization cell-matrix interactions efficient three-dimensional microenvironments. show advances invasion regulating actin dynamics at invadopodia enhancing focalized extracellular matrix proteolysis directing delivery accumulation MMP14 surface. find Nck-dependent changes are mechanistically linked to enhanced RhoA but restricted spatiotemporal activation Cdc42. Using combination protein silencing forced expression wild-type/constitutively active variants, an upstream regulator RhoA-dependent, MMP14-mediated invasion. By identifying important driver progression metastasis, these results lay groundwork future studies assessing therapeutic potential targeting aggressive cancers.