Metabolic Regulation of the Epigenome Drives Lethal Infantile Ependymoma

Michealraj, Kulandaimanuvel Antony; Kumar, Sachin; Kim, Leo J.Y.; Cavalli, Florence M.G.; Przelicki, David; Wojcik, John; Delaidelli, Alberto; Bajic, Andrea; Saulnier, Olivier; MacLeod, Graham; Vellanki, Ravi N.; Vladoiu, Maria C.; Guilhamon, Paul; Ong, Winnie Peitee; Lee, John J.Y.; Jiang, Yanqing; Holgado, Borja L.; Rasnitsyn, Alex; Malik, Ahmad; Tsai, Ricky; Richman, Cory; Juraschka, Kyle; Haapasalo, Joonas; Wang, Evan Y.; Antonellis, Pasqualino De; Suzuki, Hiromichi; Farooq, Hamza; Balin, Polina; Kharas, Kaitlin; Ommeren, Randy Van; Sirbu, Olga; Rastan, Avesta; Krumholtz, Stacey; Ly, Michelle; Ahmadi, M. Amir; Deblois, Geneviève; Srikanthan, Dilakshan; Luu, Betty; Loukides, James; Wu, Xiaochong; Garzia, Livia; Ramaswamy, Vijay; Kanshin, Evgeny; Sánchez-Osuna, María; El-Hamamy, Ibrahim; Coutinho, Fiona J.; Prinos, Panagiotis; Singh, Sheila K.; Donovan, Laura; Daniels, Craig; Schramek, Daniel; Tyers, Mike; Weiss, Samuel; Stein, Lincoln; Lupien, Mathieu; Wouters, Bradly G.; Garcia, Benjamin A.; Arrowsmith, C.H.; Sorensen, Poul H.; Angers, Stéphane; Jabado, Nada; Dirks, Peter B.; Mack, Stephen C.; Agnihotri, Sameer; Rich, Jeremy; Taylor, Michael D.

doi:10.1016/j.cell.2020.04.047

Cited by 86 publications

(96 citation statements)

References 78 publications

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“…Although adult-onset cancers are often linked to lifestyle and environmental risk factors while heritable and in utero exposures predominate in pediatric cancers, very few non-genetic risk factors have been identified for CNS malignancies [ 39 ]. While pediatric ependymomas have distinct genomic profiles from their adult counterparts, most notably in the epigenetically-driven EPN-PF-A subgroup that was not associated with telomere length in our analyses, telomerase reactivation has been observed to varying degrees across ependymoma subgroups and ages of onset [ 23 , 30 , 35 ].…”

Section: Discussionmentioning

confidence: 99%

“…Our observation that genetic predisposition to longer LTL is associated with adolescent-onset and adult-onset ependymoma, but not childhood-onset ependymoma, supports this multi-step model of tumorigenesis in patients ages 12 and up. Longer telomere length may be an important mediator of ependymoma risk in adolescents and adults, where the tumor is more dependent upon acquiring somatic driver mutations and does not arise from an epigenetically dysregulated developmental cell lineage [ 26 , 35 ].…”

Section: Discussionmentioning

confidence: 99%

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Genetic predisposition to longer telomere length and risk of childhood, adolescent and adult-onset ependymoma

Zhang

Ostrom

Semmes

et al. 2020

acta neuropathol commun

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Ependymoma is the third most common brain tumor in children, with well-described molecular characterization but poorly understood underlying germline risk factors. To investigate whether genetic predisposition to longer telomere length influences ependymoma risk, we utilized case–control data from three studies: a population-based pediatric and adolescent ependymoma case–control sample from California (153 cases, 696 controls), a hospital-based pediatric posterior fossa type A (EPN-PF-A) ependymoma case–control study from Toronto’s Hospital for Sick Children and the Children’s Hospital of Philadelphia (83 cases, 332 controls), and a multicenter adult-onset ependymoma case–control dataset nested within the Glioma International Case-Control Consortium (GICC) (103 cases, 3287 controls). In the California case–control sample, a polygenic score for longer telomere length was significantly associated with increased risk of ependymoma diagnosed at ages 12–19 (P = 4.0 × 10−3), but not with ependymoma in children under 12 years of age (P = 0.94). Mendelian randomization supported this observation, identifying a significant association between genetic predisposition to longer telomere length and increased risk of adolescent-onset ependymoma (ORPRS = 1.67; 95% CI 1.18–2.37; P = 3.97 × 10−3) and adult-onset ependymoma (PMR-Egger = 0.042), but not with risk of ependymoma diagnosed before age 12 (OR = 1.12; 95% CI 0.94–1.34; P = 0.21), nor with EPN-PF-A (PMR-Egger = 0.59). These findings complement emerging literature suggesting that augmented telomere maintenance is important in ependymoma pathogenesis and progression, and that longer telomere length is a risk factor for diverse nervous system malignancies.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Genetic predisposition to longer telomere length and risk of childhood, adolescent and adult-onset ependymoma

Zhang

Ostrom

Semmes

et al. 2020

acta neuropathol commun

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“…During the final stages of this work, two papers with related and partially overlapping results have appeared (Gojo et al, 2020;Michealraj et al, 2020). Based on a series of experiments involving in vitro culture of patient-derived tumor cells under hypoxic conditions, Michealraj et al (Michealraj et al, 2020) found that hypoxic programs are important drivers of pediatric PFA ependymoma tumorigenesis, and related these programs to the hypoxic environment of the early embryo. On the other hand, Gojo et al (Gojo et al, 2020) performed single-cell RNA-seq of a large cohort of pediatric ependymal tumors across multiple molecular groups and found the same tumor-derived cell differentiation trajectories for PFA ependymal tumors.…”

Section: Discussionmentioning

confidence: 99%

Cell Ecosystem and Signaling Pathways of Primary and Metastatic Pediatric Posterior Fossa Ependymoma

Aubin

Troisi

Alghalith

et al. 2020

Preprint

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Pediatric ependymoma is a devastating brain cancer marked by its relapsing pattern and lack of effective chemotherapies. This shortage of treatments is partially due to limited knowledge about ependymoma tumorigenic mechanisms. Although there is evidence that ependymoma originates in radial glia, the specific pathways underlying the progression and metastasis of these tumors are unknown. By means of single-cell transcriptomics, immunofluorescence, and in situ hybridization, we show that the expression profile of tumor cells from pediatric ependymomas in the posterior fossa is consistent with an origin in LGR5+ stem cells. Tumor stem cells recapitulate the developmental lineages of radial glia in neurogenic niches, promote an inflammatory microenvironment in cooperation with microglia, and upon metastatic progression initiate a mesenchymal program driven by reactive gliosis and hypoxia-related genes. Our results uncover the cell ecosystem of pediatric posterior fossa ependymoma and identify WNT/β-catenin and TGF-β signaling as major drivers of tumorigenesis for this cancer.

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“…Table 5). Recent genome-wide CRISPR-Cas9 inhibition screens have revealed that ITGA6 is highly and specifically essential in PFA ependymoma cell lines compared to glioblastoma (GBM) cell lines and fetal neural stem cells (fNSCs) 26,27 (Suppl. Figure 3c).…”

Section: Pfa Ependymomas Are Dependent On Integrin α6mentioning

confidence: 99%

“…Table 7). To investigate whether such potential DNA methylation-mediated insulator dysfunctions can be linked to the transcriptional activation of genes essential for PFA ependymoma, we compared our results with those of a genetic inhibition screen in PFA cell lines 26 4d) 26,27 . By genetic (CRISPR-Cas9) inhibition experiments we validated that ARL4C is highly and specifically essential for the growth of PFA ependymoma (Figure 4h) compared to RELA ependymoma and glioblastoma models (Suppl.…”

Section: Hypermethylation Disrupts Ctcf Binding In Pfa Ependymomamentioning

confidence: 99%

Oncogenic 3D genome conformations identify novel therapeutic targets in ependymoma

Okonechnikov

Camgöz

Park

et al. 2020

Preprint

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Ependymoma is a tumor of the brain or spinal cord. The two most common and aggressive molecular groups of ependymoma are the supratentorial RELA-fusion associated group and the posterior fossa ependymoma group A. In both groups, tumors occur mainly in young children and frequently recur after treatment1. Although the molecular mechanisms underlying these diseases have recently been uncovered, they remain difficult to target and innovative therapeutic approaches are urgently needed. Here, we use genome-wide chromosome conformation capture (Hi-C), complemented with CTCF (insulators) and H3K27ac (active enhancers) ChIP-seq as well as gene expression and whole-genome DNA methylation profiling in primary and relapsed ependymoma tumors and cell lines to identify chromosomal rearrangements and regulatory mechanisms underlying aberrant expression of genes that are essential for ependymoma tumorigenesis. In particular, we observe the formation of new topologically associating domains (‘neo-TADs’) by intra- and inter-chromosomal structural variants, tumor-specific 3D chromatin complexes of regulatory elements, and the replacement of CTCF insulators by DNA hyper-methylation as novel oncogenic mechanisms in ependymoma. Through inhibition experiments we validated that the newly identified genes, including RCOR2, ITGA6, LAMC1, and ARL4C, are highly essential for the survival of patient-derived ependymoma models in a disease subtype-specific manner. Thus, this study identifies potential novel therapeutic vulnerabilities in ependymoma and extends our ability to reveal tumor-dependency genes and pathways by oncogenic 3D genome conformations even in tumors that lack known genetic alterations.

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Metabolic Regulation of the Epigenome Drives Lethal Infantile Ependymoma

Cited by 86 publications

References 78 publications

Genetic predisposition to longer telomere length and risk of childhood, adolescent and adult-onset ependymoma

Genetic predisposition to longer telomere length and risk of childhood, adolescent and adult-onset ependymoma

Cell Ecosystem and Signaling Pathways of Primary and Metastatic Pediatric Posterior Fossa Ependymoma

Oncogenic 3D genome conformations identify novel therapeutic targets in ependymoma

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