Abstract 2349: Integrin α6β4 contributes to HGF-stimulated migration and invasion by promoting autocrine EGFR signaling in pancreatic cancer

Abstract

Abstract The lethality of pancreatic cancer is due to elevated incidences of invasion and metastasis. Previous studies from our lab and others show that pro-invasive integrin α6β4 is upregulated in early stage pancreatic cancer, maintained during tumor progression and, in turn, promotes chemotactic migration and invasion toward HGF. To gain insight into the mechanisms governing how integrin α6β4 promotes these processes, we performed Affymetrix Gene Chip analysis on Panc-1 clones with differing levels of integrin α6β4 expression. After statistical processing, we found 582 genes altered by integrin α6β4 signaling. From these results, we found that high integrin α6β4-expressing Panc1 clones substantially enhanced expression of genes affecting epidermal growth factor receptor (EGFR) signaling. The genes upregulated by integrin α6β4 included EGFR, EGF-like ligands amphiregulin (AREG) and epiregulin (EREG), ectodomain cleavage proteases ADAMTS1, MMP1, and hyaluronan synthase 3. The upregulation of these genes was confirmed by real-time PCR, immunoblot analysis and/or ELISA. Stable overexpression of integrin β4 in low integrin β4 expressing cells increased the levels of AREG and EREG by real-time PCR. We further tested the role of autocrine EGFR signaling by pretreating cells with EGFR blocking antibodies (LA1) or EGFR-specific protein tyrosine kinase inhibitor (PD153035) and tested HGF-stimulated chemotaxis, chemo-invasion and invasive growth in three-dimensional culture. Interestingly, these inhibitors blocked integrin α6β4-dependent HGF-stimulated chemotaxis, invasion and invasive growth. In summary, our data suggest integrin α6β4 confers a motile and invasive phenotype to pancreatic carcinoma cells, in part, by coordinately regulating expression of key elements of autocrine EGFR signaling. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2349. doi:10.1158/1538-7445.AM2011-2349