Single-cell landscapes of primary glioblastomas and matched explants and cell lines show variable retention of inter- and intratumor heterogeneity

LeBlanc, Véronique G.; Trinh, Diane L.; Aslanpour, Shaghayegh; Hughes, Martha; Livingstone, Dorothea; Jin, Dan; Ahn, Bo Young; Blough, Michael; Cairncross, J. Gregory; Chan, Jennifer A.; Kelly, John J.; Marra, Marco A.

doi:10.1016/j.ccell.2022.02.016

Cited by 92 publications

(81 citation statements)

References 55 publications

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“…S3N). We next applied the NES algorithm to analyze a dataset derived from patient-derived explants (PDEs) (28). We found that the samples from the third generation have a high percentage of NES-high tumor cells (one-tailed Wilcoxon's rank-sum test, P=0.048) (Fig.…”

Section: A Natural Evolution Signature Is Associated With Poor Gbm Pr...mentioning

confidence: 99%

Natural Coevolution of Tumor and Immunoenvironment in Glioblastoma

Zhang

et al. 2022

Cancer Discovery

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IDH wild-type glioblastoma (GBM) has a dismal prognosis. A better understanding of tumor evolution holds the key to developing more effective treatment. Here we study glioblastoma's natural evolutionary trajectory by using rare, multifocal samples. We sequenced 61,062 single cells from eight multifocal IDH wild-type primary GBMs and defined a natural evolution signature (NES) of the tumor. We show that the NES significantly associates with the activation of transcription factors that regulate brain development, including MYBL2 and FOSL2. Hypoxia is involved in inducing NES-transition potentially via activation of the HIF1A-FOSL2 axis. High NES tumor cells could recruit and polarize bone marrow-derived macrophages through activation of the FOSL2-ANXA1-FPR1/3 axis. These polarized macrophages can efficiently suppress T cell activity and accelerate NES-transition in tumor cells. Moreover, The polarized macrophages could upregulate CCL2 to induce tumor cell migration.

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Section: A Natural Evolution Signature Is Associated With Poor Gbm Pr...mentioning

confidence: 99%

Natural Coevolution of Tumor and Immunoenvironment in Glioblastoma

Zhang

et al. 2022

Cancer Discovery

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“…In contrast to traditional mono-layer and spheroid cultures, organoids across all models can preserve intra- and intertumoral heterogeneity [ 23 , 29 , 37 ] and establish diffusion-limited oxygen gradients within the organoids similar to that in early primary tumors, which may aid in maintaining a diverse tumor cell pool [ 23 , 38 ].…”

Section: Organoids Are Superior To Prior 2d In Vitro Models In Recapi...mentioning

confidence: 99%

“…However, current organoid models only host single TME cell populations. Primary tissue-derived tumor organoids can retain tumor-resident immune cells for a short time but progressively lose them [ 29 , 37 ]. Recent insights, especially into the importance of neuronal activity and neuron–glioma interactions in glioma proliferation, highlight the need for a neuronal TME in brain tumor models [ 51 ].…”

Section: Current Limitations Of Organoidsmentioning

confidence: 99%

Three-Dimensional Cell Culture Systems in Pediatric and Adult Brain Tumor Precision Medicine

Riedel

Faria

Alfert

et al. 2022

Cancers

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Primary brain tumors often possess a high intra- and intertumoral heterogeneity, which fosters insufficient treatment response for high-grade neoplasms, leading to a dismal prognosis. Recent years have seen the emergence of patient-specific three-dimensional in vitro models, including organoids. They can mimic primary parenteral tumors more closely in their histological, transcriptional, and mutational characteristics, thus approximating their intratumoral heterogeneity better. These models have been established for entities including glioblastoma and medulloblastoma. They have proven themselves to be reliable platforms for studying tumor generation, tumor–TME interactions, and prediction of patient-specific responses to establish treatment regimens and new personalized therapeutics. In this review, we outline current 3D cell culture models for adult and pediatric brain tumors, explore their current limitations, and summarize their applications in precision oncology.

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“…tumors at bulk and single-cell levels. LeBlanc et al found that patient derived GBM explants are genetically similar to parental tumors, retain their transcriptional characteristics, and exhibit similar levels of transcriptional heterogeneity (LeBlanc et al, 2022). In contrast, glioma stem cell (GSC) lines appear to select for a subpopulation of tumor cells with more homogeneous transcriptional pro les.…”

Section: Recent Studies Have Begun To Rigorously Test What Clinical A...mentioning

confidence: 99%

Modeling nervous system tumors with human stem cells and organoids

Wang

Duan

2022

Preprint

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Nervous system cancers are the 10th leading cause of death worldwide, many of which are difficult to diagnose and exhibit varying degrees of treatment resistance. The limitations of existing cancer models such as patient-derived xenograft (PDX) models and genetically engineered mouse (GEM) models call for the development of novel preclinical cancer models to more faithfully mimic the patient’s cancer and offer additional insights. Recent advances in human stem cell biology, organoid, and genome-editing techniques allow us to model nervous system tumors in three types of next-generation tumor models: cell-of-origin models, tumor organoids, and 3D multicellular coculture models. In this review, we introduced and compared different human stem cell/organoid-derived models, and comprehensively summarized and discussed the recently developed models for various primary tumors in the central and peripheral nervous systems, including glioblastoma (GBM), H3K27M-mutant Diffuse Midline Glioma (DMG) and H3G34R-mutant High-grade Glioma (HGG), Low-grade Glioma (LGG), Neurofibromatosis Type 1 (NF1), Neurofibromatosis Type 2 (NF2), Medulloblastoma (MB), Atypical Teratoid/rhabdoid Tumor (AT/RT), and meningioma. We further compared these models with PDX and GEM models, and discussed the opportunities and challenges of precision nervous cancer modeling with human stem cells and organoids.

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Single-cell landscapes of primary glioblastomas and matched explants and cell lines show variable retention of inter- and intratumor heterogeneity

Cited by 92 publications

References 55 publications

Natural Coevolution of Tumor and Immunoenvironment in Glioblastoma

Natural Coevolution of Tumor and Immunoenvironment in Glioblastoma

Three-Dimensional Cell Culture Systems in Pediatric and Adult Brain Tumor Precision Medicine

Modeling nervous system tumors with human stem cells and organoids

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