Abstract
Pediatric high-grade gliomas (pedHGG) belong to the most aggressive cancers in children with poor prognosis due to a lack of efficient therapeutic strategies. To identify therapeutic targets, intensive research in adult high-grade gliomas identified dysregulated and tumor-driving signal-transduction pathways. The β-catenin/Wnt-signaling pathway holds promising potential as treatment option in adults to abrogate tumor cell invasion and acquisition of “cancer stem cell” characteristics. However, pedHGG frequently differ from their adult counterparts with respect to tumor genetics and biology and observations from adult neurooncology cannot automatically be translated into pediatric setting. We therefore aimed to investigate the effects of β-catenin/Wnt-signaling pathway inhibition by the novel β-catenin/CBP-antagonist ICG-001 in two different pedHGG cell line models. In contrast to adult HGG that are characterized by strong β-catenin/Wnt signaling activity, the pedHGG cell lines KNS42 and UW479 displayed only barely detectable canonical Wnt-signaling activity. Thus, inhibition of cell migration/invasion, tumorsphere- and colony formation, proliferation in vitro as well as tumor growth in vivo/ovo, by comparatively low doses of ICG-001, probably occur independent of β-catenin/Wnt-signaling. Furthermore, mRNA sequencing analyses did not confirm a significant impact of ICG-001 on β-catenin target gene transcription, but revealed strong effects on genes involved in cellular metabolic/biosynthetic processes and cell cycle progression. ICG-001 induced strong upregulation of the cell cycle regulator JDP2 which we also found to confer a better prognosis for pedHGG patients when it is highly expressed. In conclusion, ICG-001 might offer an effective treatment option for pedHGG patients independent of canonical Wnt-signaling activity.
Highlights
Tumors of the central nervous system (CNS) are among the most common pediatric malignancies, and pediatric high-grade gliomas including anaplastic astrocytoma (AA), glioblastoma (GBM), and diffuse midline glioma account for approximately 15-20% of pediatric CNS tumors
Since Pediatric high-grade gliomas (pedHGG) differ from their adult counterparts in genetically and biologically we aimed to investigate the effects of β-catenin/Wnt-signaling pathway-inhibition by the β-catenin/CBP antagonist ICG-001 in pedHGG cell lines
ICG-001 treatment significantly inhibited the ability of all pedHGG cell lines to form colonies in a dosedependent manner (Figure 1B and 1C)
Summary
Tumors of the central nervous system (CNS) are among the most common pediatric malignancies, and pediatric high-grade gliomas (pedHGG) including anaplastic astrocytoma (AA), glioblastoma (GBM), and diffuse midline glioma account for approximately 15-20% of pediatric CNS tumors. H3.3 G34R/V mutations are markedly less frequent and are preferentially found in older children, adolescents, and young adults with hemispheric HGG with no obvious association with survival [2,3,4,5]. Several studies in adult HGG, which mostly carry wildtype H3, suggested a potential impact of the canonical Wnt/β-catenin signaling pathway in the acquisition of an aggressive GBM phenotype [6,7,8]. The Wnt/βcatenin signalling pathway may potentially be important for the phenotype of pedHGG and especially those carrying H3.3 wildtype gene or H3.3 G34R/V alleles
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