The goal of this proposal is to explore whether our newly discovered mechanism of primary tumor dormancy also governs the dormancy of metastatic cells. In our human head and neck cancer cell model, high level of urokinase receptor (uPAR) expression, prevalent in many malignant tumors, can initiate a potent MAPK-ERK activating signal by directly interacting with, and activating alpha5beta1-integrin and subsequently activating EGFR. uPAR-induced EGFR activation does not require EGFR overexpression, and is EGFR-ligand independent. uPAR-activated alpha5beta1-integrins form fibronectin (FN) fibrils that block a growth inhibitory pathway through SAPK-p38 generating a high ERK/p38 balance which is favorable for in vivo growth (tumorigenicity). Binding of urokinase plasrninogen activator (uPA) to uPAR and adhesion of cells to Fig increase the strength of the signal and tumorigenicity. Down-regulation of uPAR level, or disruption of the uPAR/integrin interaction, by inhibiting the signaling pathway, forces tumor cells into persistent dormancy. We hypothesize that, to initiate proliferation, a disseminated metastatic cancer cell needs a signal from the extracellular matrix-FN and the presence on its surface of the ERK-inducing protein assembly. Our long term goal is to map the precise role that uPAR plays in dormancy induction in this and other types of tumors, and develop reagents that will disrupt the uPAR/integrin interaction, forcing metastatic cells into persistent dormancy. We propose 3 specific aims.
Aim 1 will examine whether regulation of uPAR expression level will affect dormancy of cancer cells directly at the site of metastasis and whether uPAR contributes to organ specificity of metastases. In addition, the reciprocal sites of interaction between uPAR and cdgl-integrin will be examined to provide a basis for development of new reagents aimed at induction of cancer cell dormancy.
Specific Aim 2 will examine the mechanism of the ligand-independent, but uPAR-dependent, activation of EGFR that we have discovered. This may facilitate the future identification of specific therapeutic interventions for patients subgroups in which cancer proliferation may rely on ligand-independent EGFR activation even in the absence of EGFR overexpression. Finally, in Specific Aim 3, we will conduct a pilot study on 100 head and neck (oral) carcinomas to determine whether they express uPAR and alpha5beta1 integrin and whether these tumors can activate the proliferative MAPK-ERK pathway in absence of EGFR overexpression. ? ?
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