Stalled developmental programs at the root of pediatric brain tumors

Jessa, Selin; Blanchet-Cohen, Alexis; Krug, Brian; Vladoiu, Maria C.; Coutelier, Marie; Faury, Damien; Poreau, Brice; Jay, Nicolas; Hebert, Steven C.; Monlong, Jean; Farmer, W. Todd; Donovan, Laura; Hu, Yixing; McConechy, Melissa K.; Cavalli, Florence M.G.; Mikael, Leonie G.; Ellezam, Benjamin; Richer, Maxime; Allaire, Andréa; Weil, Alexander G.; Atkinson, Jeffrey; Farmer, Jean‐Pierre; Dudley, Roy; Larouche, Valérie; Crevier, Louis; Albrecht, Steffen; Filbin, Mariella G.; Sartelet, Hervé; Lutz, Pierre-Eric; Nagy, Corina; Turecki, Gustavo; Costantino, Santiago; Dirks, Peter B.; Murai, Keith K.; Bourque, Guillaume; Ragoussis, Jiannis; Garzia, Livia; Taylor, Michael D.; Jabado, Nada; Kleinman, Claudia L.

doi:10.1038/s41588-019-0531-7

Cited by 167 publications

(212 citation statements)

References 82 publications

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“…1a). They had high expression levels of genes upregulated by the undifferentiated tumor cell population, including PFA markers like GRIA4, MECOM, and APLNR (Pajtler et al, 2015;Taylor et al, 2005), as well as DPP10, STXBP5L, and MAPK10 (Fig 1b; Benjamini-Hochberg q-value < 0.05), consistent with these populations representing tumor cells that have undergone partial cell differentiation (Jessa et al, 2019;Vladoiu et al, 2019). The proportions of tumor-derived neural stem cells and ependymal cells were strongly anticorrelated in our data (Pearson's = −0.96, p-value = 0.001, Supplementary Fig.…”

Section: Pfa Ependymoma Tumor Cells Recapitulate Neurodevelopmental Psupporting

confidence: 53%

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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Section: Pfa Ependymoma Tumor Cells Recapitulate Neurodevelopmental Psupporting

confidence: 53%

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

Aubin

Troisi

Alghalith

et al. 2020

Preprint

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“…• Some tumors (e.g., cerebellar tumors) already originate during early embryonal development (72,73). Therefore, in children, cancer prevention through lifestyle changes should not be the main focus.…”

Section: Future Research Needsmentioning

confidence: 99%

Exercise as a Potential Intervention to Modulate Cancer Outcomes in Children and Adults?

et al. 2020

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Exercise is recommended for the healthy population as it increases fitness and prevents diseases. Moreover, exercise is also applied as an adjunct therapy for patients with various chronic diseases including cancer. Childhood cancer is a rare, heterogeneous disease that differs from adult cancer. Improved therapeutic strategies have increased childhood cancer survival rates to above 80% in developed countries. Although this is higher than the average adult cancer survival rate of about 50%, therapy results often in substantial long-term side effects in childhood cancer survivors. Exercise in adult cancer patients has many beneficial effects and may slow down tumor progression and improve survival in some cancer types, suggesting that exercise may influence cancer cell behavior. In contrast to adults, there is not much data on general effects of exercise in children. Whilst it seems possible that exercise might delay cancer progression or improve survival in children as well, there is no reliable data yet to support this hypothesis. Depending on the type of cancer, animal studies of adult cancer types show that the exercise-induced increase of the catecholamines epinephrine and norepinephrine, have suppressive as well as promoting effects on cancer cells. The diverse effects of exercise in adult cancer patients require investigating whether these results can be achieved in children with cancer.

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“…Proneural TFs in glioma include OLIG1 and OLIG2 [36], whereas mesenchymal TFs are comprised of STAT3, C/EBPB and TAZ [37]. Emerging single‐cell sequencing analysis of many brain tumour types have highlighted the preservation of cell identity programmes and their continued contribution to tumorigenesis [10,38,39].…”

Section: Reverse‐engineering Enhancers To Characterize Transcriptionmentioning

confidence: 99%

Invited Review: The role and contribution of transcriptional enhancers in brain cancer

Arabzade

Stuckert

Bertrand

et al. 2020

Neuropathology Appl Neurobio

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2020) Neuropathology and Applied Neurobiology 46, 48-56 The role and contribution of transcriptional enhancers in brain cancer Genetic alterations identified across several paediatric and adult brain tumours reveal recurrent disruption of active chromatin landscapes and dysregulation of transcriptional programmes. Noncoding elements, specifically enhancers, are central to these mechanisms, and are influenced by developmental and neural gene regulatory signatures. Epigenomic and transcriptomic methods and techniques have facilitated detection of active enhancers, and characterization of brain tumours integrated with genomic structural information. These datasets have provided new insights into the mechanisms of transcriptional control that are profoundly altered in childhood and adult brain cancer; offering new ideas and molecular targets for therapeutic intervention. This review summarizes recent advances in our understanding of active transcriptional programmes of brain cancer, their impact on tumour development, and research areas for further exploration.

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Stalled developmental programs at the root of pediatric brain tumors

Cited by 167 publications

References 82 publications

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

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

Exercise as a Potential Intervention to Modulate Cancer Outcomes in Children and Adults?

Invited Review: The role and contribution of transcriptional enhancers in brain cancer

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