Abstract 4097: Protein tyrosine phosphatase SHP-2 regulates human pancreatic cancer cell biology on collagen I

Abstract

Abstract With a five year survival rate of less than 5%, pancreatic cancer stands as one of the deadliest human malignancies. There is a great need for novel therapeutic strategies for this illness, and improving our understanding of pancreatic cancer biology will be a key step in developing these therapies. The purpose of these studies is to investigate the regulation and function of the Src Homology 2 (SH2) domain containing protein tyrosine phosphatase SHP-2 in human pancreatic cancer cells and to determine its potential value as a therapeutic target for this disease. In other cellular systems, SHP-2 is crucial for integrin and receptor tyrosine kinase-mediated activation of diverse signaling pathways, regulating many of the cellular events necessary for oncogenesis, including cell division, motility, adhesion, and survival. We hypothesized that inhibition of SHP-2 function would negatively impact integrin-mediated cell signaling and biology in response to the extracellular matrix protein collagen I, an abundant component of pancreatic tumor stroma in vivo. Initial results demonstrate that SHP-2 expression and tyrosine phosphorylation/activity are elevated in pancreatic cancer cells, relative to immortalized normal human pancreatic cells. Phosphorylation of SHP-2 is further elevated in the presence of collagen I. SHP-2 tyrosine phosphorylation in pancreatic cancer cells occurrs in a Src family kinase-dependent fashion. Initial results using miRNA-mediated knock-down of SHP-2 expression indicate the importance of SHP-2 for the ability of pancreatic cancer cells to proliferate, migrate and heal cell culture wounds on collagen I. Additionally, SHP-2 knockdown cells grown on collagen I demonstate altered tyrosine phosphorylation patterns of several signal transduction proteins, including focal adhesion kinase (FAK), in comparison to controls. These data suggest, for the first time, an importance for SHP-2 in pancreatic cancer cell biology and the potential value of SHP-2 as a therapeutic target for this disease. Ongoing and future experiments will compare the effects of SHP-2 inhibition on pancreatic tumor growth in vivo. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4097.