Abstract 4013: S100A4 promotes cell migration and growth through focal adhesion kinase and Src mediated dual signaling pathways in pancreatic cancer cells.

Abstract

Abstract BACKGROUD: Pancreatic cancer is one of the deadliest types of cancer. Activation and expression of focal adhesion kinase (FAK) and Src kinase is abnormally upregulated in pancreatic cancers. The results of clinical trials targeting either Src or FAK by inhibitors are largely unknown. S100A4 is a calcium-binding protein and aberrant S100A4 expression is an independent biomarker for poor outcomes of pancreatic cancer; however, the involved mechanism is unclear. METHODS: The effects of inhibitors on FAK and Src activation, and on cell migration and growth, were examined in MiaPaca2 and S2VP10 cell lines. To determine whether FAK and Src depend on each other or independently regulate pancreatic cancer cell phenotypes, the effects of FAK or Src mutant expression were determined. The role of S100A4 on FAK and Src activation was evaluated through loss/gain approaches. The association of S100A4 expression with FAK and Src activation was determined by immunostaining on human pancreatic cancer tissue sections. RESULTS: FAK and Src kinase inhibitors blocked activation in a dose dependent manner in both MiaPaca2 and S2VP10 cells. However, it required more inhibitor to inhibit either FAK or Src in S2VP10 cells. Blocking FAK (or Src) does not completely inhibit Src (or FAK) activation. This is confirmed by the finding that FAK mutant expression completely inhibited FAK activation, but not Src activation. Similarly, Src mutant expression did not inhibit FAK activation. Downregulation of S100A4 expression significantly decreased FAK and Src activation. Importantly, increased S100A4 expression is associated with increased FAK and Src activation in pancreatic cancer. CONCLUSIONS: These data support that the Src-FAK axis forms a dual signaling pathway, and each of them contributes independently to the aggressive pancreatic cancer cell phenotype. Also, these data support that S100A4 promotes the Src-FAK dual signaling pathway which possibly leads to a feed-forward loop facilitating pancreatic tumor progression. Citation Format: Guoqiang Cai, Elizabeth H. Kerr, Meng Hu, Youfeng Yang, Donald J. Buchsbaum, William E. Grizzle, Qiang Ding. S100A4 promotes cell migration and growth through focal adhesion kinase and Src mediated dual signaling pathways in pancreatic cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4013. doi:10.1158/1538-7445.AM2013-4013