Surface Expression of Precursor N-cadherin Promotes Tumor Cell Invasion

• DOI: 10.1593/neo.10954
• Publication Date: 2015-04-23T13:03:45Z
• Authors: Deborah Maret; Eugenia Gruzglin; Mohamad Seyed Sadr; Vincent Siu; Weisong Shan; Alexander W. Koch; Nabil G. Seidah; Rolando F. Del Ma...; David R. Colman
• Keywords: Furin; Brain Neoplasms; Cell Membrane; Immunoblotting; Neoplasms. Tumors. Oncology. Including cancer and carcinogens; Glioma; Cadherins; Cell Movement; Cell Line, Tumor; Cell Adhesion; Humans; Neoplasm Invasiveness; Neoplasm Metastasis; Protein Precursors; RNA, Small Interfering; Melanoma; Protein Processing, Post-Translational; RC254-282

The expression of N-cadherin (NCAD) has been shown to correlate with increased tumor cell motility and metastasis. However, NCAD-mediated adhesion is a robust phenomenon and therefore seems to be inconsistent with the "release" from intercellular adhesion required for invasion. We show that in the most invasive melanoma and brain tumor cells, altered posttranslational processing results in abundant nonadhesive precursor N-cadherin (proNCAD) at the cell surface, although total NCAD levels remain constant. We demonstrate that aberrantly processed proNCAD promotes cell migration and invasion in vitro. Furthermore, in human tumor specimens, we find high levels of proNCAD as well, supporting an overall conclusion that proNCAD and mature NCAD coexist on these tumor cell surfaces and that it is the ratio between these functionally antagonistic moieties that directly correlates with invasion potential. Our work provides insight into what may be a widespread mechanism for invasion and metastasis and challenges the current dogma of the functional roles played by classic cadherins in tumor progression.