Abstract 763: PLAC1 interacts with FGF7 and promotes phosphorylation of FGFR2 and AKT
Authors: Diana Barea Roldan, Christoph Hartmann, Stefanie Hubich-Rau, Tim Beissert, Claudia Paret, Giuseppe Cagna, Christoph Rohde, Stefan Wöll, Ugur Sahin, Ozlem Tureci
Journal: Cancer Research (2018)

Abstract Background PLAC1 is a protein predominantly expressed in the placenta with no substantial presence in other human tissues; however, PLAC1 is aberrantly expressed in various human cancers (eg, breast cancer), and is functionally involved in the motility, migration, and invasion of cancer cells. While these functions have been linked to the PI3K/AKT pathway, the role of PLAC1 in this signaling pathway is unclear. AKT mediates cell proliferation induced by fibroblast growth factor 7 (FGF7), a specific mitogen for epithelial cells which has a significant expression in estradiol receptor-positive breast cancer. The objectives of these nonclinical studies were to investigate if/how PLAC1 is linked to the FGF7/fibroblast growth factor receptor 2IIIb (FGF2IIIb) axis, evaluate the possible role of PLAC1 in PLAC1-expressing tumor cells, and to assess the potential of PLAC1 as a therapeutic target. Methods PLAC1 protein expression and localization, as well as its interactions with FGF7 and FGFR2, were studied in human cancer cell lines by immunohistochemistry, Western blotting, and co-immunoprecipitation. To compare cell proliferation and protein phosphorylation in PLAC1-expressing versus non-expressing cells, PLAC1 expression was knocked down in the choriocarcinoma cell line, BeWo, as well as the breast cancer cell lines, SkBr3 and T47D. Results Consistent with a previous report by Massabbal et al (2005), PLAC1 was found to be coexpressed with FGF7 and FGFR2 in placenta. Increased PLAC1 expression was noted in cell lines of trophoblastic, breast, and pancreatic lineage compared with adenocarcinoma cell lines. PLAC1 localized on the cell surface and was released into the extracellular matrix where it exhibited a strong affinity for heparin, which binds to FGFs and FGF receptors facilitating FGF-receptor binding and activation of the FGFR tyrosine kinase. In cultured cells, PLAC1, FGF7, and the FGFR2 isoform FGFR2IIIb formed a trimeric complex; only FGF7, but not other FGFs, was able to interact with PLAC1, suggesting a highly specific interaction. PLAC1 knockdown models showed substantially reduced cell proliferation and phosphorylation of AKT and FGFR2 after stimulation with FGF7 compared with control cells, indicating the involvement of PLAC1 in the FGF7-induced AKT signal transduction pathway that leads to cell proliferation. Conclusions PLAC1 may play a role in tumorigenesis through the FGF7-induced pathway of cell proliferation by promoting phosphorylation of FGFR2 and AKT through interactions with FGF7, FGFR2, and heparin. Because of this function and its cancer-selective, cell-surface expression in adult human tissue, PLAC1 may be an attractive target candidate for therapeutic anticancer antibodies. Citation Format: Diana Barea Roldan, Christoph Hartmann, Stefanie Hubich-Rau, Tim Beissert, Claudia Paret, Giuseppe Cagna, Christoph Rohde, Stefan Wöll, Ugur Sahin, Ozlem Tureci. PLAC1 interacts with FGF7 and promotes phosphorylation of FGFR2 and AKT [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 763.