Cell Lineage-Based Stratification for Glioblastoma

Wang, Zilai; Sun, Duxin; Chen, Yu-Jung; Xie, Xiao‐Bi; Shi, Yufeng; Tabar, Viviane; Brennan, Cameron; Bale, Tejus; Jayewickreme, Chenura D.; Laks, Dan R.; Llaguno, Sheila Alcantara; Parada, Luis F.

doi:10.1016/j.ccell.2020.06.003

Cited by 86 publications

(85 citation statements)

References 71 publications

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“…We performed an in silico analysis in order to find TFs overexpressed in EGFRmut gliomas but with a similar expression in wild-type or amplified EGFR gliomas. The best hit was the Sex-determining region Y (SRY)-box 9 (SOX9) gene ( Figure S6A), which have been previously linked to EGFR (22,23). We found a strong upregulation of the SOX9 protein ( Figure 6A) and mRNA ( Figure 6B) in those PDXs harboring EGFR mutations.…”

Section: Egfr Mutations Modulate the Vascular Properties Of Glioma Cementioning

confidence: 80%

The genetic status of IDH1/2 and EGFR dictates the vascular landscape and the progression of gliomas

Segura-Collar

Garranzo‐Asensio

Herránz

et al. 2020

Preprint

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RationaleGlioma progression is driven by the induction of vascular alterations but how the tumor genotype influence these changes is still a pending issue. We propose to study the underlying mechanisms by which the genetic changes in isocitrate dehydrogenase 1/2 (IDH1/2) and epidermal growth factor receptor (EGFR) genes establish the different vascular profiles of gliomas.MethodsWe stratified gliomas based on the genetic status of IDH1/2 and EGFR genes. For that we used in silico data and a cohort of 93 glioma patients, where we analyzed the expression of several transcripts and proteins. For the in vitro and in vivo studies, we used a battery of primary glioblastoma cells derived from patients, as well as novel murine glioma cell lines expressing wild-type or mutant EGFR. In these models, the effect of the small molecule ibrutinib or the downregulation of CD248 and SOX9 was evaluated to establish a molecular mechanism.ResultsWe show that IDH1/2 mutations associate with a normalized vasculature. By contrast, EGFR mutations stimulate the plasticity of glioma cells and their capacity to function as pericytes in a bone-marrow and X-linked (BMX)/SOX9 dependent manner. The presence of tumor-derived pericytes stabilize the profuse vasculature and confers a growth advantage to these tumors, although they render them sensitive to pericyte-targeted molecules. Wild-type/amplified EGFR gliomas are enriched in blood vessels too, but they show a highly disrupted blood-brain-barrier due to a decreased BMX/SOX9 activation and pericyte coverage. This leads to poor nutrient supply, necrosis and hypoxia.ConclusionsThe function of tumor-derived pericytes delimitates two distinct and aggressive vascular phenotypes in IDH1/2 wild-type gliomas. Our results lay the foundations for a vascular dependent stratification of gliomas and suggest different therapeutic vulnerabilities depending on the genetic status of EGFR.Graphical Abstract. Schematic view of IDH and EGFR function in the regulation of glioma microenvironment.Mutant IDH gliomas express low levels of angiogenic molecules and have a vasculature reminiscent of normal tissue. EGFR mutations drive glioma growth by promoting tumor-to-pericyte transdifferentiation and vascular stabilization in a BMX-SOX9 dependent way. Leaky vessels with hypoxia and necrosis characterize tumors overexpressing the wild-type isoform of the receptor. These phenotypes determine the response to therapy of the different IDH wild-type gliomas.

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Section: Egfr Mutations Modulate the Vascular Properties Of Glioma Cementioning

confidence: 80%

The genetic status of IDH1/2 and EGFR dictates the vascular landscape and the progression of gliomas

Segura-Collar

Garranzo‐Asensio

Herránz

et al. 2020

Preprint

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“…Through a cross-species GSC-based stratification approach applying the mouse cell of origin (MCO) gene signature of differentially expressed genes on a large collection of human GSC cultures, we found that developmental origin could be used to stratify functionally distinct groups of patient-derived GSC cultures 22 . A recent similar cross-species approach has further corroborated the importance of cell lineage origin in GBM 23 . In all this has demonstrated that inter-tumor heterogeneity to a large extent is shaped by the intrinsic properties of the GBM cell of origin which result in highly dynamic GSCs that basically evade all current therapies.…”

Section: Introductionmentioning

confidence: 80%

Conserved cell-lineage controlled epigenetic regulation in human and mouse glioblastoma stem cells determines functionally distinct subgroups

Maturi

Jarvius

et al. 2021

Preprint

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There is ample support for developmental regulation of glioblastoma stem cells (GSCs). To further examine how cell lineage controls GSC function we have performed a cross-species epigenome analysis of mouse and human GSC cultures. We have analyzed and compared the chromatin-accessibility landscape of nine mouse GSC cultures of defined cell of origin and 60 patient-derived GSC cultures by assay for transposase-accessible chromatin using sequencing (ATAC-seq). This uncovered a variability of both mouse and human GSC cultures that was different from transcriptome analysis and better at predicting functional subgroups. In both species the chromatin accessibility-guided clusters were predominantly determined by distal regulatory element (DRE) regions, displayed contrasting sets of transcription factor binding motifs, and exhibited different functional and drug-response properties. Cross-species analysis of DRE regions in accessible chromatin revealed conserved epigenetic regulation of mouse and human GSCs. Human ATAC-seq data produced three distinct clusters with significant overlap to our previous mouse cell of origin-based stratification, where two of the clusters displayed significantly different patient survival. We conclude that epigenetic regulation of GSCs primarily is dictated by developmental origin which controls key GSC properties and affects therapeutic response.

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“…Collectively, the cell-of-origin and subsequent mutant cell behavior appear to underlie different biological and genomic phenotypes in GBM. A recent study demonstrated that distinct characteristics in transcriptome profiles, obtained from GBM animal models targeting either NSCs or oligodendrocyte lineage cells, can be used to classify IDH-wildtype GBMs into two subtypes based on the cellular origin ( 58 ). However, individual cells from the same tumor harbor different mutations and exhibit diverse transcriptional patterns and phenotypes ( 59 ), making it difficult to completely unravel cellular origins and tumor evolution processes.…”

Section: Cell-of-origin In Glioblastomamentioning

confidence: 99%

Genetic Architectures and Cell-of-Origin in Glioblastoma

Kim

Lee

2021

Front. Oncol.

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An aggressive primary brain cancer, glioblastoma (GBM) is the most common cancer of the central nervous system in adults. However, an inability to identify its cell-of-origin has been a fundamental issue hindering further understanding of the nature and pathogenesis of GBM, as well as the development of novel therapeutic targets. Researchers have hypothesized that GBM arises from an accumulation of somatic mutations in neural stem cells (NSCs) and glial precursor cells that confer selective growth advantages, resulting in uncontrolled proliferation. In this review, we outline genomic perspectives on IDH-wildtype and IDH-mutant GBMs pathogenesis and the cell-of-origin harboring GBM driver mutations proposed by various GBM animal models. Additionally, we discuss the distinct neurodevelopmental programs observed in either IDH-wildtype or IDH-mutant GBMs. Further research into the cellular origin and lineage hierarchy of GBM will help with understanding the evolution of GBMs and with developing effective targets for treating GBM cancer cells.

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Cell Lineage-Based Stratification for Glioblastoma

Cited by 86 publications

References 71 publications

The genetic status of IDH1/2 and EGFR dictates the vascular landscape and the progression of gliomas

The genetic status of IDH1/2 and EGFR dictates the vascular landscape and the progression of gliomas

Conserved cell-lineage controlled epigenetic regulation in human and mouse glioblastoma stem cells determines functionally distinct subgroups

Genetic Architectures and Cell-of-Origin in Glioblastoma

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