Deregulated Wnt/β-catenin program in high-risk neuroblastomas without MYCN amplification

Abstract

Neuroblastoma (NB) is a frequently lethal tumor of childhood. MYCN amplification accounts for the aggressive phenotype in a subset while the majority have no consistently identified molecular aberration but frequently express MYC at high levels. We hypothesized that activated Wnt/b-catenin (CTNNB1) signaling might account for this as MYC is a b-catenin transcriptional target and multiple embryonal and neural crest malignancies have oncogenic alterations in this pathway. NB cell lines without MYCN amplification express higher levels of MYC and b-catenin (with aberrant nuclear localization) than MYCNamplified cell lines. Evidence for aberrant b-catenin-TCF transcriptional activity was demonstrated using expression profiles from 73 primary NBs. Findings included increased WNT ligands (WNT1, WNT6, WNT7A, WNT10B), DVL1 and TCF7 expression in high-risk NBs without MYCN amplification, consistent with canonical b-catenin signaling. More directly, Patterns of Gene Expression and Gene Set Enrichment Analyses demonstrated b-catenin target genes (for example, MYC, PPARD, NRCAM, CD44, TCF7) as coordinately upregulated in high-risk NBs without MYCN amplification in comparison to high-risk MYCN-amplified or intermediate-risk NBs, supporting pathway activation in this subset. Thus, high-risk NBs without MYCN amplification may deregulate MYC and other oncogenic genes via altered b-catenin signaling providing a potential candidate pathway for therapeutic inhibition.

The Wnt receptor FZD1 mediates chemoresistance in neuroblastoma through activation of the Wnt/β-catenin pathway

“…The overall accumulation and preferred nuclear localization of active b-catenin as detected by confocal microscopy in both resistant cell lines, but particularly pronounced in IGRN-91-R cells, which also express extremely high Wnt signalling in chemoresistant NB M Flahaut et al levels of the Wnt receptor FZD1, provided additional confirmation of the functional Wnt/b-catenin canonical pathway in chemoresistant cells. Like others, we were unable to convincingly show b-catenin transactivation using the pTOP/pFOP-flash luciferase reporter assay (Liu et al, 2008). The inability to measure TCF/LEF transcriptional activity in these cells may be a common phenomenon in NB.…”

“…Moreover, abnormal activation of the Wnt signalling pathway could be independent of Wnt component mutations (Bafico et al, 2004;Merle et al, 2005). Recently Liu et al (2008) described activation of the pathway in the absence of activating mutations in NB cell lines and primary NBs. Therefore, upstream elements, such as the aberrantly signalling frizzled receptors and their corresponding ligands, are potential candidates for activation of the canonical Wnt pathway.…”

“…Moreover, it has been shown that overactivation of the Wnt signalling pathway is due to the overexpression of different FZD receptors in a variety of cancers (Milovanovic et al, 2004;Merle et al, 2005;Ueno et al, 2008). In NB, b-catenin has been shown to be strongly expressed and aberrantly localized in the nucleus in highly aggressive NB cells without MYCN amplification, whereas no b-catenin-specific mutations were identified (Liu et al, 2008).…”

Evaluation and Structural Basis for the Inhibition of Tankyrases by PARP Inhibitors

“…10 As compound 29 is a potent tankyrase inhibitor, it is possible that some of the observed clinical effects could be due to tankyrase inhibition especially in cases where β-catenin expression is enhanced. 20,21 Compound 10 was designed to mimic NAD + and to bind to the substrate NAD + site of ARTD1. 15 The crystal structure of 10 in complex with ARTD6 shows that the compound binds to the NAD + binding groove of ARTD6 and spans all the way from the nicotinamide binding subsite to the adenosine subsite of this cleft (Figure 3a).…”

Embryonal neural tumours and cell death

“…Amplification of MYCN occurs in a large fraction of highrisk neuroblastoma and is associated with aggressive disease in children and poor clinical outcome [6]. Moreover, constitutive activation of phosphatidylinositol 3-kinase (PI3K)/ Akt as well as activation of Wnt signalling has recently been shown in primary neuroblastomas [22][23][24]. Activation of both these signalling pathways is associated with increased MYCN expression in neuroblastoma [22,24,25].…”