Wnt activation as a therapeutic strategy in medulloblastoma

Manoranjan, Branavan; Venugopal, Chitra; Bakhshinyan, David; Adile, Ashley; Richards, Laura M.; Kameda-Smith, Michelle; Whitley, Owen; Dvorkin‐Gheva, Anna; Subapanditha, Minomi; Savage, Neil; Tatari, Nazanin; McKenna, Dillon; Bassey-Archibong, Blessing; Winegarden, Neil; Hallett, Robin; Provias, John; Yarascavitch, Blake; Ajani, Olufemi; Fleming, Adam; Bader, Gary D.; Pugh, Trevor J.; Doble, Bradley W.; Singh, Sheila K.

doi:10.1038/s41467-020-17953-4

Cited by 37 publications

(26 citation statements)

References 53 publications

(92 reference statements)

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“…Wnt ligands have been reported to exert different cellular effects depending on types of receptors present on Wnt-responsive cells ( van Amerongen et al, 2012b , 2008 ). Although Wnt activation is classically viewed as a mitogenic and self-renewal signal in otic and non-otic tissues ( Jansson et al, 2015 ; Logan and Nusse, 2004 ), it has also been shown to suppress proliferation and tumor formation in subtypes of medulloblastoma and breast cancer ( Green et al, 2013 ; Manoranjan et al, 2020 ). Likewise, our results indicate that the cellular effects of β-catenin stabilization are highly context-dependent.…”

Section: Discussionmentioning

confidence: 99%

Opposing effects of Wnt/β-catenin signaling on epithelial and mesenchymal cell fate in the developing cochlea

et al. 2021

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During embryonic development, the otic epithelium and surrounding periotic mesenchymal cells originate from distinct lineages and coordinate to form the mammalian cochlea. Epithelial sensory precursors within the cochlear duct first undergo terminal mitosis before differentiating into sensory and non-sensory cells. In parallel, periotic mesenchymal cells differentiate to shape the lateral wall, modiolus and pericochlear spaces. Previously, Wnt activation was shown to promote proliferation and differentiation of both otic epithelial and mesenchymal cells. Here, we fate-mapped Wnt-responsive epithelial and mesenchymal cells in mice and found that Wnt activation resulted in opposing cell fates. In the post-mitotic cochlear epithelium, Wnt activation via β-catenin stabilization induced clusters of proliferative cells that dedifferentiated and lost epithelial characteristics. In contrast, Wnt-activated periotic mesenchyme formed ectopic pericochlear spaces and cell clusters showing a loss of mesenchymal and gain of epithelial features. Finally, clonal analyses via multi-colored fate-mapping showed that Wnt-activated epithelial cells proliferated and formed clonal colonies, whereas Wnt-activated mesenchymal cells assembled as aggregates of mitotically quiescent cells. Together, we show that Wnt activation drives transition between epithelial and mesenchymal states in a cell type-dependent manner.

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Section: Discussionmentioning

confidence: 99%

Opposing effects of Wnt/β-catenin signaling on epithelial and mesenchymal cell fate in the developing cochlea

et al. 2021

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“…It is known that WNT/β-catenin signaling has a widespread influence in cellular differentiation, tumor initiation, and progression [ 40 , 41 ]. This suggests there is a closer relationship between WNT/β-catenin signaling and non-WNT medulloblastomas (i.e., group 3 and group 4 medulloblastoma) [ 42 ].…”

Section: Discussionmentioning

confidence: 99%

Melanotic Neuroectodermal Tumor of Infancy (MNTI) and Pineal Anlage Tumor (PAT) Harbor A Medulloblastoma Signature by DNA Methylation Profiling

Lopez‐Nunez

Alaggio

John

et al. 2021

Cancers

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MNTI is a rare tumor of indeterminate histogenesis and molecular signature. We performed methylation and copy number variation (CNV) profiles in patients with MNTI (n = 7) and PAT (n = 1) compared to the methylation brain tumor classifier v11b4 (BT-C) and the medulloblastoma (MB) classifier group 3/4 v1.0 (MB3/4-C). The patients’ mean age was 8 months (range: 4–48). The BT-C classified five MNTIs and one PAT (relapse) as class family MB-G3/G4, subclass group 3 (score: >0.9). The remaining two MNTIs and PAT (primary) were classified as class family plexus tumor, subclass pediatric (scores: >0.45). The MB3/4-C classified all MNTIs as high-risk MB-G3, Subtype II (score: >0.45). The primary PAT was classified as subtype III (score: 0.99) and its relapse as subtype II/III. MNTI and PAT clustered close to MB-G3. CNV analysis showed multiple rearrangements in one PAT and two MNTIs. The median follow-up was 54 months (four MNTIs in remission, one PAT died). In conclusion, we demonstrated that MNTI shares a homogenous methylation profile with MB-G3, and possibly with PAT. The role of a multipotent progenitor cell (i.e., early cranial neural crest cell) in their histogenesis and the influence of the anatomical site, tumor microenvironment, and other cytogenetic events in their divergent biologic behavior deserve further investigation.

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“…Moreover, the pathway is known to be actively involved in the modulation of the synaptic function to maintain the basal neural activity [ 91 ]. Consequently, alterations in Wnt signaling have been implicated in many neurodegenerative and neuro-oncological diseases, raising the importance of the specific pathway targeting for efficient treatment strategies [ 92 , 93 , 94 , 95 , 96 , 97 ]. Besides, the misexpression of pseudogenes has been linked to various human diseases, including several cancers [ 98 , 99 , 100 , 101 , 102 , 103 ].…”

Section: Discussionmentioning

confidence: 99%

Nradd Acts as a Negative Feedback Regulator of Wnt/β-Catenin Signaling and Promotes Apoptosis

et al. 2021

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Wnt/β-catenin signaling controls many biological processes for the generation and sustainability of proper tissue size, organization and function during development and homeostasis. Consequently, mutations in the Wnt pathway components and modulators cause diseases, including genetic disorders and cancers. Targeted treatment of pathway-associated diseases entails detailed understanding of the regulatory mechanisms that fine-tune Wnt signaling. Here, we identify the neurotrophin receptor-associated death domain (Nradd), a homolog of p75 neurotrophin receptor (p75NTR), as a negative regulator of Wnt/β-catenin signaling in zebrafish embryos and in mammalian cells. Nradd significantly suppresses Wnt8-mediated patterning of the mesoderm and neuroectoderm during zebrafish gastrulation. Nradd is localized at the plasma membrane, physically interacts with the Wnt receptor complex and enhances apoptosis in cooperation with Wnt/β-catenin signaling. Our functional analyses indicate that the N-glycosylated N-terminus and the death domain-containing C-terminus regions are necessary for both the inhibition of Wnt signaling and apoptosis. Finally, Nradd can induce apoptosis in mammalian cells. Thus, Nradd regulates cell death as a modifier of Wnt/β-catenin signaling during development.

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Wnt activation as a therapeutic strategy in medulloblastoma

Cited by 37 publications

References 53 publications

Opposing effects of Wnt/β-catenin signaling on epithelial and mesenchymal cell fate in the developing cochlea

Opposing effects of Wnt/β-catenin signaling on epithelial and mesenchymal cell fate in the developing cochlea

Melanotic Neuroectodermal Tumor of Infancy (MNTI) and Pineal Anlage Tumor (PAT) Harbor A Medulloblastoma Signature by DNA Methylation Profiling

Nradd Acts as a Negative Feedback Regulator of Wnt/β-Catenin Signaling and Promotes Apoptosis

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