Abstract 3257: Nodal signalling in choriocarcinoma cells

Abstract

Abstract Choriocarcinoma is an aggressive cancer that arises when the invasion of placental trophoblast cells into the endometrium becomes dysregulated. Trophoblast invasion is a complex phenomenon, dependent on cues that drive trophoblast invasion, as well as factors to ensure that placental invasion does not extend beyond the myometrium. Nodal, a member of the TGF-β superfamily, is expressed throughout the endometrium during the peri-implantation period and in invasive trophoblast cells. However, Nodal's exact role in placental function is unclear. Nodal signals by activating the ALK4/7, ActRIIB and Cripto-1 receptor complex and emerging evidence suggests that its signalling strength can be controlled at the level of receptor endocytosis into signaling endosomes. Two key regulators of receptor endocytosis and cell invasion are the α-arrestins, multifunctional scaffolding proteins and Ral GTPases, members of the Ras superfamily. Ral can bind to ActRIIB, and its activity can be regulated by Ras, as well as by α-arrestins, in a Ras-independent manner. We thus hypothesized that Nodal promotes trophoblast invasion via a α-arrestin/Ral-mediated pathway. The specific objectives of my study are to (i) determine the effects of Nodal on trophoblast invasion, (ii) elucidate a role for α-arrestin / Ral signaling in regulating Nodal-induced trophoblast invasion. We found that Nodal stimulates the invasion of both the non-malignant HTR-8SV/neo trophoblast and JAR choriocarcinoma cells using Matrigel-coated transwell chamber assays. Interestingly, we found that the JAR choriocarcinoma cells responded differently to Nodal in that while HTR-8SV/neo invasion returned to baseline levels, JAR choricocarcinoma cells continued to invade even at the higher concentrations of Nodal (100ng/mL & 500ng/mL). For this reason, we decided to look at potential differences in the regulation of Nodal-induced invasion between the non-malignant HTR-8SV/neo trophoblast and JAR choricoarcinoma cell lines. We found that the JAR choriocarcinoma cells differentially expressed Ral and α-arrestin proteins compared to the HTR-8SV/neo cells. Additonally, endogenous Ral and α-arrestins associate with the ALK4 and 7 receptors, and knockdown of these molecules impaired Nodal-induced invasion. Thus, our data reveal a novel function for Nodal in modulating trophoblast invasion via a α-arrestin/Ral signaling pathway. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3257. doi:1538-7445.AM2012-3257