Abstract 1943: Integrin α6β4 promotes autocrine EGFR signaling to stimulate migration and invasion toward HGF

Abstract

Abstract Integrin α6β4 is upregulated in pancreatic adenocarcinomas where it contributes to carcinoma cell invasion, in part, through its coordinated modulation of the transcriptome. Here, we find that integrin α6β4 signaling dramatically upregulates the expression of several genes involved in the epidermal growth factor receptor (EGFR) pathway, including amphiregulin (Areg), epiregulin (Ereg), and ectodomain cleavage protease MMP1. Notably, these genes correlate well with integrin α6β4 expression in publicly available pancreatic cancer databases. We previously reported that integrin α6β4 promotes HGF-stimulated migration and invasion; therefore, we tested the role of autocrine EGFR signaling in these processes. We discovered that blocking EGFR signaling with EGFR-specific blocking antibodies or an EGFR tyrosine kinase inhibitor hindered HGF-stimulated pancreatic carcinoma cell chemotaxis and invasive growth in three-dimensional culture. Furthermore, we found that both Areg and Ereg are required for these autocrine effects, as knocking down either ligand prevented migration and invasion. Notably, AsPC1 cells, isolated from abdominal metastases, are not dependent on EGFR signaling for migration or invasion; thus suggesting a mechanism exists for circumventing EGFR dependency. We also demonstrated that HGF stimulates the secretion of Areg, which is dependent on integrin signaling pathways including MAPK, PI3K and PKC and that Areg was transported to the leading edge of cells treated with HGF. Moreover, MMP activity and integrin α6β4 signaling are required for Areg secretion. Finally, we found that EGFR is phosphorylated in response to HGF stimulation which was dependent on EGFR protein kinase activity; however, Met phosphorylation in response to HGF was unaffected by EGFR signaling. Taken together, we show that integrin α6β4 stimulates invasion by promoting autocrine EGFR signaling through the upregulation of key genes and facilitating HGF-stimulated EGFR ligand secretion. Citation Format: Brittany L. Carpenter, Min Chen, Teresa Knifley, Kelley A. Davis, Susan M. Harrison, Rachel L. Stewart, Kathleen L. O'Connor. Integrin α6β4 promotes autocrine EGFR signaling to stimulate migration and invasion toward HGF. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1943. doi:10.1158/1538-7445.AM2015-1943