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Wnt activation as a therapeutic strategy in medulloblastoma

ABSTRACT: Medulloblastoma (MB), the most common malignant pediatric brain tumor, is defined by four molecular subgroups (Wnt, Shh, Group 3, Group 4) based on transcriptional and epigenetic profiles. Wnt MB accounts for 10% of cases with the majority harboring somatic CTNNB1 mutations and chromosomal alterations for monosomy 6. Clinically, Wnt MBs have the most favorable prognosis with a >95% 5-year survivorship. By contrast, non-Wnt MBs are characterized by metastatic disease, increased rates of recurrence, and intermediate-poor overall survivorship. Given that Wnt MBs represent the only subgroup in which metastasis is not indicative of a poor prognosis, it has been suggested that Wnt signaling may contribute to their remarkable response to therapy. Using primary patient-derived MB brain tumor-initiating cell (BTIC) lines, we have characterized intrinsic differences in the tumor-initiating capacity of Wnt and non-Wnt MBs. In this work, we aimed to discover if Wnt activation in non-Wnt MBs could serve as a rationale for therapy employing a novel substrate-competitive peptide Wnt agonist. Our preclinical work establishes activated Wnt signaling as an innovative treatment paradigm with high clinical utility in childhood MB and provides evidence for the context-specific tumor suppressive function of the Wnt/β-catenin pathway.

ORGANISM(S): Homo sapiens

PROVIDER: GSE131473 | GEO | 2020/06/27

REPOSITORIES: GEO

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Project description:Medulloblastomas (MBs) are cerebellar tumors that can be classified into molecularly distinct subgroups that differ in pathology and prognosis. The mechanisms that underlie subgroup specification are largely unknown. While human SHH MBs express MYCN, Group3 (G3) MBs are associated with c-MYC (MYC) overexpression and often show metastasis that confers a poor prognosis. Although MYC proteins are thought to be functionally exchangeable, ectopic expression of Myc or N-myc in Trp53-/-;Cdkn2c-/- cerebellar granule neuron progenitors (GNPs) induces G3 and SHH MBs, respectively, demonstrating that each Myc protein has distinct biological properties. We now show that Myc and N-myc differ in their affinity to Miz1 and that Myc, but not N-myc, effectively recruits Miz1 to its target sites on chromatin. The interaction of Myc with Miz1 is required for the genesis of G3 MB. Myc suppresses ciliogenesis and âreprogramsâ the transcriptome of SHH-dependent GNPs to stem-like cells by repressing genes highly expressed in SHH MB via Miz1. Consistently, target genes of Myc/Miz1 are repressed in human G3 MBs but not in other MB subgroups. Collectively, the data show that the interaction of Myc with Miz1 is a defining hallmark of G3 MB development. In this study, we show that Myc and N-myc differ in their affinity for Miz1, and Myc/Miz1 interaction is required for Group3 medulloblastoma (MB). The gene expression profiles of these tumors were compared to our previously published Group3 MB model as well as SHH model of MB (Kawachi et al., 2012, Cancer Cell). Cerebellar granule neuron progenitors (GNPs) [dka220-222] from postnatal (P) 6 Math1-GFP;Trp53-/-;Cdkn2c-/-. For SHH medulloblastomas, [dka204-206] and [blm015-017 or dka050-dka051], spontaneous medulloblastomas from Cdkn2c-/-;Trp53Fl/Fl;Nestin-Cre (Kawachi et al., 2012, Cancer Cell) and Ptch1+/-;Cdkn2c-/- (Uziel et al., 2005, Genes Dev) were used, respectively. Myc- [dka201-203] and MycV394D (termed MycVD thereafter)- [bvo017-bvo023] tumors were from Trp53-/-;Cdkn2c-/- cerebella of P6-P7 pups. Myc/ÎPOZ tumors [bvo002-bvo006] were obtained from Trp5Fl/Fl;Miz1ÎPOZ/POZ;Nestin-Cre cerebella of P6-P7 pups.

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Wnt activation as a therapeutic strategy in medulloblastoma

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