The developmental origin of brain tumours: a cellular and molecular framework

Azzarelli, Roberta; Simons, Benjamin D.; Philpott, Anna

doi:10.1242/dev.162693

Cited by 112 publications

(94 citation statements)

References 151 publications

(209 reference statements)

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“…The idea that tumor initiation, progression and regrowth after treatment are sustained by a subpopulation of cancer cells, the glioblastoma stem cells (GSCs), has been crucial to our current understating of glioblastoma (GBM) biology (Swartling et al, 2015;Alcantara Llaguno et al, 2016;Azzarelli et al, 2018;Hakes and Brand, 2019;Lu et al, 2019). Glioblastoma is a highly aggressive brain tumor characterized by elevated intratumor heterogeneity, which could be potentially attributed to variations in GSC behavior and stochastic consequences of their hierarchical growth pattern.…”

Section: Introductionmentioning

confidence: 99%

Organoid Models of Glioblastoma to Study Brain Tumor Stem Cells

Azzarelli

2020

Front. Cell Dev. Biol.

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Glioblastoma represents an aggressive form of brain cancer characterized by poor prognosis and a 5-year survival rate of only 3-7%. Despite remarkable advances in brain tumor research in the past decades, very little has changed for patients, due in part to the recurrent nature of the disease and to the lack of suitable models to perform genotype-phenotype association studies and personalized drug screening. In vitro culture of cancer cells derived from patient biopsies has been fundamental in understanding tumor biology and for testing the effect of various drugs. These cultures emphasize the role of in vitro cancer stem cells (CSCs), which fuel tumor growth and are thought to be the cause of relapse after treatment. However, it has become clear over the years that a 2D monolayer culture of these CSCs has certain disadvantages, including the lack of heterogeneous cell-cell and cell-environment interactions, which can now be partially overcome by the introduction of 3D organoid cultures. This is a novel and expanding field of research and in this review, I describe the emerging 3D models of glioblastoma. I also discuss their potential to advance our knowledge of tumor biology and CSC heterogeneity, while debating their current limitations.

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Section: Introductionmentioning

confidence: 99%

Organoid Models of Glioblastoma to Study Brain Tumor Stem Cells

Azzarelli

2020

Front. Cell Dev. Biol.

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“…Appearance of tumor 10 heterogeneity from an initial homogenous population of Chinmo + Imp + tNBs, population dynamics, and permanent tumor growth result from a division pattern in which Chinmo + Imp + tNBs have a preference for symmetric self-renewing divisions (~64% of divisions) while also being able to generate Syp + tNBs via asymmetric divisions (they self-renew while giving rise to a Syp + tNB in ~15% of divisions), or symmetric differentiation divisions (they give rise to two Syp + tNBs in ~21% of divisions ). In addition, 15 we have shown that Syp + tNBs do not give rise to Chinmo + Imp + tNBs and have a high tendency to enter quiescence. Given that the co-expression of Chinmo and Imp is sufficient to promote unlimited NB selfrenewal (Narbonne-Reveau et al, 2016), this division pattern is sufficient to promote unlimited NB amplification, creating hierarchical tumors with Chinmo + Imp + tNBs acting as CSC-like cells while Syp + tNBs behave as TAP-like cells ( Figure 7E).…”

Section: Discussion: a Subverted Developmental Transition Triggers Himentioning

confidence: 78%

“…Consequently, it has been proposed that neural cancers may be "locked" into to a developmental program (Azzarelli et al, 2018). This attractive hypothesis could be particularly relevant for pediatric cancers that often originate from growing tissues and require much less mutations than adult cancers to be initiated and become aggressive (Grobner et al, 2018;Scotting et al, 2005;Vogelstein et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Cooption of antagonistic RNA-binding proteins establishes cell hierarchy in Drosophila neuro-developmental tumors

Genovese

Clément

Gaultier

et al. 2018

Preprint

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The mechanisms that govern the hierarchical organization of tumors are still poorly understood, especially in highly heterogeneous neural cancers. Previously, we had shown that aggressive neural 15 tumors can be induced upon dedifferentiation of susceptible intermediate progenitors produced during early development (Narbonne-Reveau et al., 2016). Using clonal analysis, stochastic modelling and single-cell transcriptomics, we now find that such tumors rapidly become heterogeneous, containing progenitors with different proliferative potentials. We demonstrate that tumor heterogeneity emerges from the deregulated transition between two antagonistic RNA-binding proteins, Imp and Syncrip, that switch 20 neural progenitors from a default self-renewing to a differentiation-prone state during development.Consequently, aberrant maintenance of Imp confers a cancer stem cell-like identity as Imp + progenitors sustain tumor growth while being able to continuously generate Syncrip + progenitors. The latter exhibit limited self-renewal likely due to Syncrip-mediated metabolic exhaustion. This study provides an example of how a subverted developmental transition establishes a hierarchical tumor. 25

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“…We combined several methods using massively parallel DNA sequencing to assay chromatin accessibility, active or repressive modification of histones to map regulatory sites instructive for gene expression in gliomas. Gliomas arise from neural stem cells, progenitors or dedifferentiated nervous system cells (Azzarelli et al, 2018). It is expected to find active chromatin regions characteristic of the tissue from which tumor originated as well as tumor specific activity in the data obtained from the bulk tumor material.…”

Section: Discussionmentioning

confidence: 99%

Mapping chromatin accessibility and active regulatory elements reveals new pathological mechanisms in human gliomas

Stępniak

Machnicka

Mieczkowski

et al. 2019

Preprint

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Chromatin structure and accessibility, and combinatorial binding of transcription factors to regulatory elements in genomic DNA control transcription. Genetic variations in genes encoding histones, epigenetics-related enzymes or modifiers affect chromatin structure/dynamics and result in alterations in gene expression contributing to cancer development or progression. Gliomas are brain tumors frequently associated with epigenetics-related gene deregulation. We performed whole-genome mapping of chromatin accessibility, histone modifications, DNA methylation patterns and transcriptome analysis simultaneously in multiple tumor samples to unravel novel epigenetic dysfunctions driving gliomagenesis. Based on the results of the integrative analysis of the acquired profiles, we created an atlas of active enhancers and promoters in benign and malignant gliomas. We explored these elements and intersected with Hi-C data to uncover molecular SignificanceEpigenetics-driven deregulation of gene expression accompanies cancer development, but its comprehensive characterization in cancer patients is fragmentary. We performed wholegenome profiling of gene expression, open chromatin, histone modifications and DNAmethylation profiles in the same samples from benign and malignant gliomas. Our study provides a first comprehensive atlas of active regulatory elements in gliomas, which allowed identification of the functional enhancers and promoters in patient samples. This comprehensive approach revealed epigenetic patterns influencing gene expression in benign gliomas and a new pathogenic mechanism involving FOXM1-driven network in glioblastomas. This atlas provides a common set of elements for cross-comparisons of existing and new datasets, prompting novel discoveries and better understanding of gliomagenesis. Highlights We provide an atlas of cis-regulatory elements active in human gliomas  Enhancer-promoter contacts operating in gliomas are revealed  Diverse enhancer activation is pronounced in malignant gliomas  Chromatin loop activates FOXM1-ANXA2R pathological network in glioblastomas.

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The developmental origin of brain tumours: a cellular and molecular framework

Cited by 112 publications

References 151 publications

Organoid Models of Glioblastoma to Study Brain Tumor Stem Cells

Organoid Models of Glioblastoma to Study Brain Tumor Stem Cells

Cooption of antagonistic RNA-binding proteins establishes cell hierarchy in Drosophila neuro-developmental tumors

Mapping chromatin accessibility and active regulatory elements reveals new pathological mechanisms in human gliomas

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