Frizzled2 signaling regulates growth of high-risk neuroblastomas by interfering with β-catenin-dependent and β-catenin-independent signaling pathways.
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.
Division of Cell and Developmental Biology, Center for Anatomy and Cell Biology, Medical University of Vienna, Vienna, A-1090, Austria.
Karin
K
Zins
Apeiron Biologics AG, Vienna, A-1030, Austria.
Romana
R
Schäfer
Department of Anesthesiology and Operative Intensive Care Medicine, Kepler University Hospital, Linz, A-4040, Austria.
Patrick
P
Paulus
Department of Anesthesiology and Operative Intensive Care Medicine, Kepler University Hospital, Linz, A-4040, Austria.
Silvia
S
Dobler
Division of Cell and Developmental Biology, Center for Anatomy and Cell Biology, Medical University of Vienna, Vienna, A-1090, Austria.
Nazak
N
Fakhari
Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Montebello, Oslo, N-0310, Norway.
Mouldy
M
Sioud
Division of Cell and Developmental Biology, Center for Anatomy and Cell Biology, Medical University of Vienna, Vienna, A-1090, Austria.
Seyedhossein
S
Aharinejad
Division of Cell and Developmental Biology, Center for Anatomy and Cell Biology, Medical University of Vienna, Vienna, A-1090, Austria.|Comprehensive Cancer Center (CCC), Medical University of Vienna, Vienna, A-1090, Austria.
Dietmar
D
Abraham
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D051157:Frizzled Receptors / Q000378:metabolism*; D064593:Heterografts; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009447:Neuroblastoma / Q000378:metabolism* / Q000473:pathology*; D060449:Wnt Signaling Pathway / Q000502:physiology*
C489742:FZD2 protein, human; D051157:Frizzled Receptors
Frizzled2; Wnt signaling; neuroblastoma; xenograft model