Single-cell RNA-seq reveals that glioblastoma recapitulates a normal neurodevelopmental hierarchy

Couturier, Céline; Ayyadhury, Shamini; Le, Phuong Uyen; Nadaf, Javad; Monlong, Jean; Riva, Gabriele; Allache, Redouane; Baig, Salma; Yan, Xiaohua; Bourgey, Mathieu; Lee, Changseok; Wang, Yu Chang David; Yong, V. Wee; Guiot, Marie‐Christine; Najafabadi, Hamed S.; Mišić, Bratislav; Antel, Jack; Bourque, Guillaume; Ragoussis, Jiannis; Petrecca, Kevin

doi:10.1038/s41467-020-17186-5

Cited by 335 publications

(355 citation statements)

References 83 publications

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“…While stemness in cancer is widely debated, in silico modeling reveals the need to effectively kill stem-like cells in breast cancer to prevent recurrence ( 23 ). Furthermore, recent research shows glioma cells do exhibit de facto qualities of stemness, including the ability to differentiate into multiple functionally distinct phenotypes recreating a neurodevelopmental hierarchy ( 31 ). Our patient-derived glioblastoma stem cells were isolated using non-adherent culture, and expression of common stemness markers like CD133, often used for GSC isolation, is not guaranteed in the absence of this positive selection step.…”

Section: Discussionmentioning

confidence: 99%

A patient-designed tissue-engineered model of the infiltrative glioblastoma microenvironment

Cornelison

Yuan

Tate

et al. 2020

Preprint

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Glioblastoma is an aggressive brain cancer characterized by diffuse infiltration. Infiltrated glioma cells persist in the brain post-resection where they interact with glial cells and experience interstitial fluid flow. We recreate this infiltrative microenvironment in vitro based on resected patient tumors and examine malignancy metrics (invasion, proliferation, and stemness) in the context of cellular and biophysical factors and therapies. Our 3D tissue-engineered model comprises patient-derived glioma stem cells, human astrocytes and microglia, and interstitial fluid flow. We found flow contributes to all outcomes across seven patient-derived lines, and glial effects are driven by CCL2 and differential glial activation. We conducted a six-drug screen using four outcomes and find expression of putative stemness marker CD71, opposed to viability IC50, significantly predicts murine xenograft survival. Our results dispute the paradigm of viability as predictive of drug efficacy. We posit this patient-centric, infiltrative tumor model is a novel advance towards translational personalized medicine.

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Section: Discussionmentioning

confidence: 99%

A patient-designed tissue-engineered model of the infiltrative glioblastoma microenvironment

Cornelison

Yuan

Tate

et al. 2020

Preprint

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“…The inherent heterogeneity and complexity of these invasive stem cell-driven cancers have severely impeded therapeutic advancement. Emerging evidence, supported by single-cell RNA sequencing, suggests that the dedifferentiated glioma stem cell state characteristic of brain tumours arises from the disruption of developmental networks essential for controlling neural stem cell fate and brain formation [ 86 , 87 ]. As in neural stem cells, MYC likely promotes glioma by amplifying transcriptional programs promoting renewal and hampering differentiation.…”

Section: Brain Tumours Are Driven By Cancer Stem Cellsmentioning

confidence: 99%

MYC in Brain Development and Cancer

Zaytseva

Kim

Quinn

2020

IJMS

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The MYC family of transcriptional regulators play significant roles in animal development, including the renewal and maintenance of stem cells. Not surprisingly, given MYC’s capacity to promote programs of proliferative cell growth, MYC is frequently upregulated in cancer. Although members of the MYC family are upregulated in nervous system tumours, the mechanisms of how elevated MYC promotes stem cell-driven brain cancers is unknown. If we are to determine how increased MYC might contribute to brain cancer progression, we will require a more complete understanding of MYC’s roles during normal brain development. Here, we evaluate evidence for MYC family functions in neural stem cell fate and brain development, with a view to better understand mechanisms of MYC-driven neural malignancies.

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“…The malignancy scoring approach builds upon the approaches used by (Tirosh et al, 2016) and (Couturier et al, 2020) for classifying cells as either transformed, malignant cells or untransformed cells within the tumor microenvironment (Supplementary Methods).…”

Section: Malignancy Statusmentioning

confidence: 99%

CHARTS: A web application for characterizing and comparing tumor subpopulations in publicly available single-cell RNA-seq datasets

Bernstein

Collins

et al. 2020

Preprint

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BackgroundSingle-cell RNA-seq (scRNA-seq) enables the profiling of genome-wide gene expression at the single-cell level and in so doing facilitates insight into and information about cellular heterogeneity within a tissue. Perhaps nowhere is this more important than in cancer, where tumor and tumor microenvironment heterogeneity directly impact development, maintenance, and progression of disease. While publicly available scRNA-seq cancer datasets offer unprecedented opportunity to better understand the mechanisms underlying tumor progression, metastasis, drug resistance, and immune evasion, much of the available information has been underutilized, in part, due to the lack of tools available for aggregating and analysing these data.ResultsWe present CHARacterizing Tumor Subpopulations (CHARTS), a computational pipeline and web application for analyzing, characterizing, and integrating publicly available scRNA-seq cancer datasets. CHARTS enables the exploration of individual gene expression, cell type, malignancy-status, differentially expressed genes, and gene set enrichment results in subpopulations of cells across multiple tumors and datasets.ConclusionCHARTS is an easy to use, comprehensive platform for exploring single-cell subpopulations within tumors across the ever-growing collection of public scRNA-seq cancer datasets. CHARTS is freely available at charts.morgridge.org.

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Single-cell RNA-seq reveals that glioblastoma recapitulates a normal neurodevelopmental hierarchy

Cited by 335 publications

References 83 publications

A patient-designed tissue-engineered model of the infiltrative glioblastoma microenvironment

A patient-designed tissue-engineered model of the infiltrative glioblastoma microenvironment

MYC in Brain Development and Cancer

CHARTS: A web application for characterizing and comparing tumor subpopulations in publicly available single-cell RNA-seq datasets

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