Tumor heterogeneity and tumor-microglia interactions in primary and recurrent IDH1-mutant gliomas

Blanco-Carmona, Enrique; Narayanan, Ashwin; Hernandez, Inmaculada; Nieto, Juan C.; Elosua-Bayes, Marc; Sun, Xueyuan; Schmidt, Claudia; Pamir, Necmettin; Özduman, Koray; Herold-Mende, Christel; Pagani, Francesca; Cominelli, Manuela; Taranda, Julian; Wick, Wolfgang; von Deimling, Andreas; Poliani, Pietro Luigi; Rehli, Michael; Schlesner, Matthias; Heyn, Holger; Turcan, Şevin

doi:10.1016/j.xcrm.2023.101249

Cited by 10 publications

(2 citation statements)

References 62 publications

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“…The chromatin landscape in TAM-MGs has been explored using single-cell ATAC-seq in human and mouse gliomas, which has the advantage of being able to separate subpopulations of immune cells from other tumor cells, but is limited by uneven sequencing coverage and transcript biases. Nonetheless, chromatin accessibility distinguishing TAM-MGs from other infiltrating immune cell populations 30 and different TAM-MG phenotypic states across gliomas 31 have been reported. However, the active enhancers and their interacting transcription factors regulating the human TAM-MG state have not been explored.…”

Section: Resultsmentioning

confidence: 99%

The inactive X chromosome drives sex differences in microglial inflammatory activity in human glioblastoma

Tharp,

Han,

Balak

et al. 2024

Preprint

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SummaryBiological sex is an important risk factor in cancer, but the underlying cell types and mechanisms remain obscure. Since tumor development is regulated by the immune system, we hypothesize that sex-biased immune interactions underpin sex differences in cancer. The male-biased glioblastoma multiforme (GBM) is an aggressive and treatment-refractory tumor in urgent need of more innovative approaches, such as considering sex differences, to improve outcomes. GBM arises in the specialized brain immune environment dominated by microglia, so we explored sex differences in this immune cell type. We isolated adult human TAM-MGs (tumor-associated macrophages enriched for microglia) and control microglia and found sex-biased inflammatory signatures in GBM and lower-grade tumors associated with pro-tumorigenic activity in males and anti-tumorigenic activity in females. We demonstrated that genes expressed or modulated by the inactive X chromosome facilitate this bias. Together, our results implicate TAM-MGs, specifically their sex chromosomes, as drivers of male bias in GBM.

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Section: Resultsmentioning

confidence: 99%

The inactive X chromosome drives sex differences in microglial inflammatory activity in human glioblastoma

Tharp,

Han,

Balak

et al. 2024

Preprint

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“…As well, the “oligodendrocyte-like” differentiation state was shown to be “stalled” with an aberrantly blocked myelination transcriptional program [ 223 ]. Such analyses have been enhanced by longitudinal studies in primary/recurrent IDH-mutant gliomas specimens, tracking changes and stability in persistent and recurrent tumor subpopulations [ 21 ]. Additionally, multi-omic analyses, including scRNA-seq plus scATAC-seq [ 3 , 12 , 223 ] or scRNA-seq plus single-cell DNA methylome [ 39 , 103 ], have enhanced transcriptional cell state diversity analysis and helped to reconstruct more accurate transcription factor regulatory networks.…”

Section: Defining Tumor Heterogeneity Using Single-cell Transcriptomicsmentioning

confidence: 99%

Genetic and epigenetic instability as an underlying driver of progression and aggressive behavior in IDH-mutant astrocytoma

Richardson,

Walker,

Hambardzumyan

et al. 2024

Acta Neuropathol

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In recent years, the classification of adult-type diffuse gliomas has undergone a revolution, wherein specific molecular features now represent defining diagnostic criteria of IDH-wild-type glioblastomas, IDH-mutant astrocytomas, and IDH-mutant 1p/19q-codeleted oligodendrogliomas. With the introduction of the 2021 WHO CNS classification, additional molecular alterations are now integrated into the grading of these tumors, given equal weight to traditional histologic features. However, there remains a great deal of heterogeneity in patient outcome even within these established tumor subclassifications that is unexplained by currently codified molecular alterations, particularly in the IDH-mutant astrocytoma category. There is also significant intercellular genetic and epigenetic heterogeneity and plasticity with resulting phenotypic heterogeneity, making these tumors remarkably adaptable and robust, and presenting a significant barrier to the design of effective therapeutics. Herein, we review the mechanisms and consequences of genetic and epigenetic instability, including chromosomal instability (CIN), microsatellite instability (MSI)/mismatch repair (MMR) deficits, and epigenetic instability, in the underlying biology, tumorigenesis, and progression of IDH-mutant astrocytomas. We also discuss the contribution of recent high-resolution transcriptomics studies toward defining tumor heterogeneity with single-cell resolution. While intratumoral heterogeneity is a well-known feature of diffuse gliomas, the contribution of these various processes has only recently been considered as a potential driver of tumor aggressiveness. CIN has an independent, adverse effect on patient survival, similar to the effect of histologic grade and homozygous CDKN2A deletion, while MMR mutation is only associated with poor overall survival in univariate analysis but is highly correlated with higher histologic/molecular grade and other aggressive features. These forms of genomic instability, which may significantly affect the natural progression of these tumors, response to therapy, and ultimately clinical outcome for patients, are potentially measurable features which could aid in diagnosis, grading, prognosis, and development of personalized therapeutics.

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Co-expression of immune checkpoints in glioblastoma revealed by single-nucleus RNA sequencing and spatial transcriptomics

Yuan,

Chen,

Jin

et al. 2024

Computational and Structural Biotechnology Journal

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Tumor heterogeneity and tumor-microglia interactions in primary and recurrent IDH1-mutant gliomas

Cited by 10 publications

References 62 publications

The inactive X chromosome drives sex differences in microglial inflammatory activity in human glioblastoma

The inactive X chromosome drives sex differences in microglial inflammatory activity in human glioblastoma

Genetic and epigenetic instability as an underlying driver of progression and aggressive behavior in IDH-mutant astrocytoma

Co-expression of immune checkpoints in glioblastoma revealed by single-nucleus RNA sequencing and spatial transcriptomics

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