"The aims of this Fellowship is to identify protein tyrosine phosphatases (PTPs) that are required for the ability of N-cadherin to increase tumor cell migration and to test whether these molecules can ultimately serve as future drug targets.
A majority of cancer mortalities is due to metastases, and identifying drug targets to prevent tumor cell invasion and migration is urgent. During the epithelial to mesenchymal transition, expression of the non-epithelial N-cadherin is upregulated, whereas E-cadherin expression is downregulated- a phenomenon known as the cadherin switch. In the breast carcinoma cell line MCF-7, this process is accompanied by an increased cell motility that is directly dependent on N-cadherin expression. In vivo studies demonstrated that N-cadherin expressing MCF-7 tumors showed increased invasiveness and metastasis, as well as increased responsiveness to fibroblast growth factor (FGF). PTPs are known regulators of both receptor tyrosine kinases and cadherin function. Dynamic (de)phosphorylation of components of the N-cadherin adhesion complex may be the key event in regulating the migratory properties of breast carcinoma cells.
MCF-7 cells stably expressing N-cadherin have already been obtained, which display increased migration towards FGF in vitro. From the N-cadherin expressing cell line, cells where PTPs are stably downregulated using shRNAi will be generated. With this model system, the effect of individual PTPs on N-cadherin-mediated adhesion, migration and invasion will be assayed in vitro. In addition, these cells will be used to identify PTPs regulating FGF receptor phosphorylation and signal transduction. Cell lines displaying altered properties in these assays will be selected for further in vivo studies. Following injection into nude mice, the tumor growth and metastasis will be assayed. Using state of the art multiphoton confocal microscopy, the N-cadherin-induced invasion can be visualized over time in live animals."
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