Frizzled2 signaling regulates growth of high-risk neuroblastomas by interfering with β-catenin-dependent and β-catenin-independent signaling pathways

// Karin Zins 1 , Romana Schäfer 2 , Patrick Paulus 3 , Silvia Dobler 3 , Nazak Fakhari 1 , Mouldy Sioud 4 , Seyedhossein Aharinejad 1 , Dietmar Abraham 1, 5 1 Division of Cell and Developmental Biology, Center for Anatomy and Cell Biology, Medical University of Vienna, Vienna, A-1090, Austria 2 Apeiron Biologics AG, Vienna, A-1030, Austria 3 Department of Anesthesiology and Operative Intensive Care Medicine, Kepler University Hospital, Linz, A-4040, Austria 4 Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Montebello, Oslo, N-0310, Norway 5 Comprehensive Cancer Center (CCC), Medical University of Vienna, Vienna, A-1090, Austria Correspondence to: Dietmar Abraham, email: dietmar.abraham@meduniwien.ac.at Keywords: Frizzled2, Wnt signaling, neuroblastoma, xenograft model Received: March 09, 2016      Accepted: May 30, 2016      Published: June 15, 2016 ABSTRACT Frizzled2 (FZD2) is a receptor for Wnts and may activate both canonical and non-canonical Wnt signaling pathways in cancer. However, no studies have reported an association between FZD2 signaling and high-risk NB so far. Here we report that FZD2 signaling pathways are critical to NB growth in MYCN -single copy SK-N-AS and MYCN -amplified SK-N-DZ high-risk NB cells. We demonstrate that stimulation of FZD2 by Wnt3a and Wnt5a regulates β-catenin-dependent and –independent Wnt signaling factors. FZD2 blockade suppressed β-catenin-dependent signaling activity and increased phosphorylation of PKC, AKT and ERK in vitro , consistent with upregulation of β-catenin-independent signaling activity. Finally, FZD2 small interfering RNA knockdown suppressed tumor growth in murine NB xenograft models associated with suppressed β-catenin-dependent signaling and a less vascularized phenotype in both NB xenografts. Together, our study suggests a role for FZD2 in high-risk NB cell growth and provides a potential candidate for therapeutic inhibition in FZD2-expressing NB patients.