Abstract C254: Suppression of E-cadherin function leads to deregulation of FAK and Src to direct squamous cell carcinoma progression

Abstract

Abstract Advanced stages of epithelial carcinogenesis are linked to loss of intercellular adhesion, but it remains unclear how alterations in cell-cell and cell-matrix adhesions are coordinated to promote the early stages of cancer development. To address this, we used 3D tissue models that mimic human premalignant disease, and studied the impact of E-cadherin suppression in early stage, epithelial tumor cells (HaCaT-II-4) on the expression and activity of Focal Adhesion Kinase (FAK) and Src kinase and on tumor cell motility and invasiveness. Suppression of E-cadherin function triggered elevated expression of FAK, increased tyrosine phosphorylation of FAK and Src, and redirected these protein tyrosine kinases to a perinuclear distribution. Pharmacological inhibition of FAK or Src, by either Tyrphostin AG1007 or PP2, reduced their phosphorylation, and reversibly inhibited tumor cell motility in 2D, monolayer cultures. Decreased FAK or Src expression by lentivirus-mediated shRNA restored E-cadherin expression and cell-cell adhesion and inhibited cell migration. 3D, bioengineered tissues harboring E-cadherin-deficient-II-4 cells in which FAK or Src were depleted, demonstrated increased membrane localization of E-cadherin, normalization of tissue phenotype and suppression of tumor cell invasion into the underlying matrix. When these 3D tissues were grafted to the dorsum of immunocompromised mice, down-regulation of FAK or Src resulted in suppression of tumor growth in vivo. Specifically, decreased Src expression reversed the tumor phenotype from high-grade, aggressive and infiltrative SCC to low-grade, well-differentiated and demarcated tumor islands. Collectively, our findings demonstrate that E-cadherin suppression directs the biological behavior of early stage, E-cadherin-deficient tumor cells in vitro and SCC progression in vivo, through modulation of FAK and Src expression and/or activity. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C254.