Abstract 1625: CUB domain-containing protein 1 (CDCP1) promotes metastatic phenotype in pancreatic ductal adenocarcinoma

Abstract

Abstract CUB domain-containing protein 1 (CDCP1) is a transmembrane glycoprotein that is overexpressed and highly tyrosine phosphorylated in multiple cancer types including pancreatic ductal adenocarcinoma (PDAC), a highly lethal disease. CDCP1 has been implicated in the promotion of metastases, namely cancer cell migration, invasion, and resistance to anoikis. In addition, prior studies in other cancer cell lines have shown that hypoxia inducible factors (HIF-1α and HIF-2α), which are key regulators of metastasis, induce both expression of CDCP1 and phosphorylation at tyrosine 734. The role of CDCP1 and the mechanisms that regulate CDCP1 still need further elucidation in PDAC. In this study, we demonstrated that CDCP1 is highly expressed and tyrosine phosphorylated in PDAC cell lines MiaPaCa2, PaTu89902, and Panc-1 cell lines compared to the non-tumorigenic pancreatic ductal cell line HPNE. shRNA knockdown of CDCP1 showed a reduction in the phosphorylation of Src and PKC-delta. To determine whether HIF regulates CDCP1 in PDAC, we used PDAC cell lines that stably express shRNAs targeting HIF-1α and HIF-2α. Hypoxia induced an increase in CDCP1 expression in a HIF-1α-dependent fashion. Additionally, CDCP1 knockdown in PaTu8902, a highly metastatic PDAC line, impaired cancer cell invasion by transwell invasion assay but did not show resistance to anoikis by soft agar assay. To validate our data in vivo, we performed intra-pancreatic injection of shCDCP1 PaTu8902 cells and scramble control transfected with GFP/luciferase into nude mice. Live imaging demonstrated that 2 weeks after initial injection resulted in decreased tumor establishment in mice injected with the shCDCP1 cell line compared to control. We propose that CDCP1 expression and tyrosine phosphorylation in PDAC is mediated by hypoxia inducible factors and that CDCP1 confers invasive properties in vitro and may play a role in initial tumor establishment in vivo. Based on these results, CDCP1 is a promising novel target for PDAC. Citation Format: Sunnie Kim, Brooke Emerling, Benjamin Hopkins, Ryan Loughran, Salva Naranjos, Lewis Cantley. CUB domain-containing protein 1 (CDCP1) promotes metastatic phenotype in pancreatic ductal adenocarcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1625.