Notch pathway in ependymoma RELA-fused subgroup: upregulation and association with cancer stem cells markers expression

Magalhães, Taciani de Almeida; Cruzeiro, Gustavo Alencastro Veiga; Sousa, Graziella Ribeiro de; Silva, Keteryne Rodrigues da; Lira, Régia Caroline Peixoto; Scrideli, Carlos Alberto; Tone, Luíz Gonzaga; Valera, Elvis Terci; Borges, Kleiton Silva

doi:10.1038/s41417-019-0122-x

Cited by 16 publications

(8 citation statements)

References 15 publications

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“…However, when we applied Notch inhibitor to treat BXD-1425-EPN cells, no significant effect on cell survival and growth was observed (data not shown). de Almeida Magalhães T et al also had the same observation in their study [2]. They claimed although Notch inhibitor treatment did not change cell proliferation, apoptosis and colony formation of ST-EPN-RELA, it induced down-regulation of cancer stem cell markers.…”

Section: Discussionmentioning

confidence: 52%

“…Interestingly, the top enriched pathway was Notch signaling. Looking back at the ST-EPN-RELA gene list (Supplementary Table 2, online resource), 15 Notch signaling genes stood out, ADAM12, CCND1, DLK1, DVL1, DVL2, HDAC1, HES1, HES5, JAG1, JAG2, LFNG, LNX1, MFAP2, NOTCH1 and PSENEN, further demonstrating Notch signaling might play a significant role in ST-EPN-RELA oncogenesis [2].…”

Section: C11orf95-rela Modulates Chromatin State and Mediates Chromatmentioning

confidence: 99%

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C11orf95-RELA reprograms 3D epigenome in supratentorial ependymoma

Zhu

Jillette

et al. 2020

Acta Neuropathol

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Supratentorial ependymoma (ST-EPN) is a type of malignant brain tumor mainly seen in children. Since 2014, it has been known that an intrachromosomal fusion C11orf95-RELA is an oncogenic driver in ST-EPN [Parker et al. Nature 506:451–455 (2014); Pietsch et al. Acta Neuropathol 127:609–611 (2014)] but the molecular mechanisms of oncogenesis are unclear. Here we show that the C11orf95 component of the fusion protein dictates DNA binding activity while the RELA component is required for driving the expression of ependymoma-associated genes. Epigenomic characterizations using ChIP-seq and HiChIP approaches reveal that C11orf95-RELA modulates chromatin states and mediates chromatin interactions, leading to transcriptional reprogramming in ependymoma cells. Our findings provide important characterization of the molecular underpinning of C11orf95-RELA fusion and shed light on potential therapeutic targets for C11orf95-RELA subtype ependymoma.

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Section: Discussionmentioning

confidence: 52%

Section: C11orf95-rela Modulates Chromatin State and Mediates Chromatmentioning

confidence: 99%

C11orf95-RELA reprograms 3D epigenome in supratentorial ependymoma

Zhu

Jillette

et al. 2020

Acta Neuropathol

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“…On day 15, cells were fixed with methanol and stained using GIEMSA. A detailed protocol can be found in studies previously published by our group [ 13 , 14 ].…”

Section: Methodsmentioning

confidence: 99%

YAP1 Is a Potential Predictive Molecular Biomarker for Response to SMO Inhibitor in Medulloblastoma Cells

Cruzeiro

Magalhães

Sousa

et al. 2021

Cancers

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Advances in genomics have led to the identification of twelve relevant molecular subtypes within medulloblastoma (MB). The alpha subtype of Sonic hedgehog-driven MB is resistant to therapy (including smoothened inhibitors) due to activation of genes from the non-canonical SHH pathway, such as MYCN, YAP1, or TP53. Using retrospective cohort microarray data, we found that YAP1 is overexpressed in SHH alpha MB and patients profiled as resistant to SMO inhibitors compared to good responders. Here, we performed YAP1 depletion via CRISPR/Cas9 in two in vitro models of SHH-like MB cells and found that this protein is involved in responsiveness to the SMO inhibitor regarding proliferation, apoptosis, and colony formation. Further, considering the synergic combination of YAP1 depletion with SMO inhibition, we assessed single-cell RNA-seq data from five patients and found that SMO and YAP1 are enriched within cells of SHH MB. Importantly, our data suggest that YAP1 is not only a reliable biomarker for cellular response to SMOi but may indicate prospective testing of combination therapy using YAP1 and SMO inhibitors in preclinical models of SHH MB.

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“…Unlike wild-type RELA, RELA fusion oncoproteins are constitutively localized in the nucleus, where they drive aberrant activation of NF-κB target gene transcription in vitro and in vivo [ 24 ]. Recent key studies integrating epigenomic and transcriptomic mapping have demonstrated that a number of non-canonical NF-κB transcriptional programs, such as Notch, MAPK, and focal adhesion networks, are critical actors of ST-RELA formation, in addition to the canonical NF-κB signaling [ 104 , 105 , 106 ]. Contrary to the initial hypothesis positing that the RELA partner drives the transcriptional activity of RELA fusion proteins, recent chromatin interaction-based analyses support the idea that it is the ZFTA moiety that shuttles the RELA component to the nucleus and dictates the RELA fusion binding affinity across the genome, so as to orchestrate the transcription of ependymoma-associated genes in collaboration with RELA targets [ 105 , 106 , 107 , 108 ].…”

Section: Determinants Of Ithmentioning

confidence: 99%

Cell-of-Origin and Genetic, Epigenetic, and Microenvironmental Factors Contribute to the Intra-Tumoral Heterogeneity of Pediatric Intracranial Ependymoma

Servidei

Lucchetti

Navarra

et al. 2021

Cancers

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Intra-tumoral heterogeneity (ITH) is a complex multifaceted phenomenon that posits major challenges for the clinical management of cancer patients. Genetic, epigenetic, and microenvironmental factors are concurrent drivers of diversity among the distinct populations of cancer cells. ITH may also be installed by cancer stem cells (CSCs), that foster unidirectional hierarchy of cellular phenotypes or, alternatively, shift dynamically between distinct cellular states. Ependymoma (EPN), a molecularly heterogeneous group of tumors, shows a specific spatiotemporal distribution that suggests a link between ependymomagenesis and alterations of the biological processes involved in embryonic brain development. In children, EPN most often arises intra-cranially and is associated with an adverse outcome. Emerging evidence shows that EPN displays large intra-patient heterogeneity. In this review, after touching on EPN inter-tumoral heterogeneity, we focus on the sources of ITH in pediatric intra-cranial EPN in the framework of the CSC paradigm. We also examine how single-cell technology has shed new light on the complexity and developmental origins of EPN and the potential impact that this understanding may have on the therapeutic strategies against this deadly pediatric malignancy.

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Notch pathway in ependymoma RELA-fused subgroup: upregulation and association with cancer stem cells markers expression

Cited by 16 publications

References 15 publications

C11orf95-RELA reprograms 3D epigenome in supratentorial ependymoma

C11orf95-RELA reprograms 3D epigenome in supratentorial ependymoma

YAP1 Is a Potential Predictive Molecular Biomarker for Response to SMO Inhibitor in Medulloblastoma Cells

Cell-of-Origin and Genetic, Epigenetic, and Microenvironmental Factors Contribute to the Intra-Tumoral Heterogeneity of Pediatric Intracranial Ependymoma

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