Enhancement of Cell Death in High-Grade Glioma Cells

ABSTRACTBackgroundDespite extensive molecular characterization, we lack a comprehensive understanding of lineage identity, differentiation, and proliferation in high-grade gliomas (HGGs). We sampled the cellular milieu of HGGs with massively-parallel single-cell RNA-Seq.ResultsWhile HGG cells can resemble glia or even immature neurons and form branched lineage structures, mesenchymal transformation results in unstructured populations. Glioma cells in a subset of mesenchymal tumors lose their neural lineage identity, express inflammatory genes, and co-exist with marked myeloid infiltration, reminiscent of molecular interactions between glioma and immune cells established in animal models. Additionally, we discovered a tight coupling between lineage resemblance and proliferation among malignantly transformed cells. Glioma cells that resemble oligodendrocyte progenitors, which proliferate in the brain, are often found in the cell cycle. Conversely, glioma cells that resemble astrocytes, neuroblasts, and oligodendrocytes, which are non-proliferative in the brain, are generally non-cycling in tumors.ConclusionsThese studies reveal a relationship between cellular identity and proliferation in HGG and distinct population structures that reflects the extent of neural and non-neural lineage resemblance among malignantly transformed cells.

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In Vitro Evaluation of Iodine-125-Labeled Monoclonal Antibody (MAb 425) in Human High-Grade Glioma Cells

American Journal of Clinical Oncology ◽

10.1097/00000421-199612000-00015 ◽

1996 ◽

Vol 19 (6) ◽

pp. 601-608 ◽

Cited By ~ 6

Author(s):

Jacqueline G. Emrich ◽

Hans Bender ◽

Reiner Class ◽

Jeffrey Eshleman ◽

Curtis Miyamoto ◽

...

Keyword(s):

Monoclonal Antibody ◽

Glioma Cells ◽

High Grade Glioma ◽

High Grade ◽

In Vitro Evaluation ◽

Iodine 125

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Autophagy as a Potential Therapy for Malignant Glioma

Pharmaceuticals ◽

10.3390/ph13070156 ◽

2020 ◽

Vol 13 (7) ◽

pp. 156 ◽

Cited By ~ 2

Author(s):

Angel Escamilla-Ramírez ◽

Rosa A. Castillo-Rodríguez ◽

Sergio Zavala-Vega ◽

Dolores Jimenez-Farfan ◽

Isabel Anaya-Rubio ◽

...

Keyword(s):

Cell Proliferation ◽

Cell Death ◽

Tumor Cells ◽

Glioma Cells ◽

High Grade ◽

Therapeutic Approaches ◽

Genetic Changes ◽

A Cell ◽

Autophagic Process ◽

Marked Resistance

Glioma is the most frequent and aggressive type of brain neoplasm, being anaplastic astrocytoma (AA) and glioblastoma multiforme (GBM), its most malignant forms. The survival rate in patients with these neoplasms is 15 months after diagnosis, despite a diversity of treatments, including surgery, radiation, chemotherapy, and immunotherapy. The resistance of GBM to various therapies is due to a highly mutated genome; these genetic changes induce a de-regulation of several signaling pathways and result in higher cell proliferation rates, angiogenesis, invasion, and a marked resistance to apoptosis; this latter trait is a hallmark of highly invasive tumor cells, such as glioma cells. Due to a defective apoptosis in gliomas, induced autophagic death can be an alternative to remove tumor cells. Paradoxically, however, autophagy in cancer can promote either a cell death or survival. Modulating the autophagic pathway as a death mechanism for cancer cells has prompted the use of both inhibitors and autophagy inducers. The autophagic process, either as a cancer suppressing or inducing mechanism in high-grade gliomas is discussed in this review, along with therapeutic approaches to inhibit or induce autophagy in pre-clinical and clinical studies, aiming to increase the efficiency of conventional treatments to remove glioma neoplastic cells.

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PDTM-21. MULTI-MODAL PROFILING OF PEDIATRIC HIGH-GRADE GLIOMA SINGLE CELLS USING PATCH-SEQ

Neuro-Oncology ◽

10.1093/neuonc/noz175.797 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi191-vi191

Author(s):

Shawn Gillespie ◽

Marlene Arzt ◽

Pamelyn Woo ◽

Michelle Monje

Keyword(s):

Single Cell ◽

Single Cells ◽

Glioma Cells ◽

High Grade Glioma ◽

Neural Circuitry ◽

Extracellular Potassium ◽

High Grade ◽

Transcriptional Profiles ◽

Pediatric High Grade Glioma ◽

Developmental Hierarchy

Abstract Pediatric and adult high-grade gliomas are characterized by extensive intra-tumoral transcriptional heterogeneity. When measured by single cell RNA sequencing, gliomas reveal themselves as continuums of stemness and differentiation programs with important implications for therapy, but to date this transcriptional information has not been directly linked to physiological behaviors of cells. Recent work from our group establishes the electrical integration of glioma cells into neural circuitry. One subpopulation of glioma cells participates in glutamatergic synaptic communication with neurons, and a distinct subpopulation of cells sense and respond to extracellular potassium flux of neuronal networks by an entirely distinct mechanism. Our data support a model in which both modes of electrical communication are critical to glioma growth, but current associations between the electrophysiological properties of a cell, its transcriptional profile and developmental state are correlational in nature. Patch-seq is needed to clarify the relationship between transcriptional profiles of quiescent/cycling stem-like cells and the observed electrophysiological behaviors. Put more simply, patch-seq will clarify where the synaptically-connected glioma cells exist along a developmental hierarchy. METHODS Here, we adapt a recently described technique called patch-seq to record the electrophysiological profiles of individual pediatric high-grade glioma cells by whole cell patch-clamp and subsequently isolate their mRNA for single cell sequencing by smart-seq2 and analysis using Seurat. In this way, we couple electrophysiological and transcriptomic profiles to unambiguously assign functional identities to cells with transcriptional profiles along a developmental hierarchy. RESULTS We report the successful adaptation of patch-seq for use with patient-derived diffuse intrinsic pontine glioma (DIPG) xenografts in acute brain slice preparations, enabling evaluation of single glioma cells integrated in intact neural circuitry. CONCLUSIONS Data synthesizing the electrophysiological and transcriptomic profiles of single glioma cells in the context of the developmental hierarchy will be presented.

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Piperlongumine treatment inactivates peroxiredoxin 4, exacerbates endoplasmic reticulum stress, and preferentially kills high-grade glioma cells

Neuro-Oncology ◽

10.1093/neuonc/nou088 ◽

2014 ◽

Vol 16 (10) ◽

pp. 1354-1364 ◽

Cited By ~ 30

Author(s):

Tae Hyong Kim ◽

Jieun Song ◽

Sung-Hak Kim ◽

Arav Krishnavadan Parikh ◽

Xiaokui Mo ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Endoplasmic Reticulum Stress ◽

Glioma Cells ◽

High Grade Glioma ◽

High Grade

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Clinically Explored Virus-Based Therapies for the Treatment of Recurrent High-Grade Glioma in Adults

Biomedicines ◽

10.3390/biomedicines9020138 ◽

2021 ◽

Vol 9 (2) ◽

pp. 138

Author(s):

Amanda V. Immidisetti ◽

Chibueze D. Nwagwu ◽

David C. Adamson ◽

Nitesh V. Patel ◽

Anne-Marie Carbonell

Keyword(s):

Glioma Cells ◽

High Grade Glioma ◽

Treatment Modalities ◽

Host Immune System ◽

High Grade ◽

Treatment Paradigm ◽

Multiple Trials ◽

Glioma Antigens ◽

New Treatment ◽

Preclinical And Clinical Studies

As new treatment modalities are being explored in neuro-oncology, viruses are emerging as a promising class of therapeutics. Virotherapy consists of the introduction of either wild-type or engineered viruses to the site of disease, where they exert an antitumor effect. These viruses can either be non-lytic, in which case they are used to deliver gene therapy, or lytic, which induces tumor cell lysis and subsequent host immunologic response. Replication-competent viruses can then go on to further infect and lyse neighboring glioma cells. This treatment paradigm is being explored extensively in both preclinical and clinical studies for a variety of indications. Virus-based therapies are advantageous due to the natural susceptibility of glioma cells to viral infection, which improves therapeutic selectivity. Furthermore, lytic viruses expose glioma antigens to the host immune system and subsequently stimulate an immune response that specifically targets tumor cells. This review surveys the current landscape of oncolytic virotherapy clinical trials in high-grade glioma, summarizes preclinical experiences, identifies challenges associated with this modality across multiple trials, and highlights the potential to integrate this therapeutic strategy into promising combinatory approaches.

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H3.3K27M Mutation Promotes The Migration and Invasion of Glioma Cells By Activating β-Catenin/USP1 Signaling

10.21203/rs.3.rs-1215261/v1 ◽

2022 ◽

Author(s):

Zhiyuan Sun ◽

Yufu Zhu ◽

Xia Feng ◽

Xiaoyun Liu ◽

Kunlin Zhou ◽

...

Keyword(s):

Glioma Cells ◽

High Grade Glioma ◽

Diffuse Intrinsic Pontine Glioma ◽

Migration And Invasion ◽

Mrna Levels ◽

High Grade ◽

Protein Levels ◽

Adult Glioma

Abstract H3.3K27M is a newly identified molecular pathology marker in glioma and is especially correlated with the malignancy of diffuse intrinsic pontine glioma (DIPG). In recent years, accumulating research has revealed that other types of glioma also contain the H3.3K27M mutation. However, the role of H3.3K27M in high-grade adult glioma, which is the most malignant glioma, has not been investigated. In this study, we focused on exploring the expression and function of H3.3K27M in high-grade adult glioma patients. We found that H3.3K27M is partly highly expressed in high-grade glioma tissues. Then, we introduced H3.3K27M into H3.3 wild-type glioma cells, U87 cells and LN229 cells. We found that H3.3K27M did not regulate the growth of glioma in vitro and in vivo; however, the survival of mice with transplanted tumors was significantly reduced. Further investigation revealed that H3.3K27M expression mainly promoted the migration and invasion of glioma cells. Moreover, we certified that H3.3K27M overexpression enhanced the protein levels of ꞵ-catenin and p-ꞵ-catenin, the protein and mRNA levels of ubiquitin-specific protease 1 (USP1), and the protein level of enhancer of zeste homolog 2 (EZH2). Importantly, the ꞵ-catenin inhibitor XAV-939 significantly attenuated the upregulation of the aforementioned proteins. Overall, the H3.3K27M mutation is present in a certain proportion of high-grade glioma patients and facilitates a poor prognosis by promoting the metastasis of glioma by regulating the ꞵ-catenin/USP1/EZH2 pathway.

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