Journal articles: 'Glioma Stem-like Cells'

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Ventosa, Maria, Padma Kadiyala, Stephen Carney, Maria Castro, and Pedro Lowenstein. "GENE-32. SYNTHETIC LETHAL INTERACTIONS WITH IDH1R132H IN GLIOMA STEM-LIKE CELLS." Neuro-Oncology 21, Supplement_6 (November 2019): vi104. http://dx.doi.org/10.1093/neuonc/noz175.434.

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Abstract Gliomas are the most frequently diagnosed human primary brain tumors. Mutations in Isocitrate Dehydrogenase (IDH) 1 occur in the vast majority of low grade gliomas and secondary high grade glioblastomas. A single amino acid missense mutation in IDH1 at arginine 132 (R132H) is an early event in tumor development. IDH1R132H leads to the production of the oncometabolite 2-R-2-hydroxyglutarate. However the exact roles played by IDH1R132H in the development and malignant transformation of the tumors remain unclear. Further studies are required to determine optimal therapeutic strategies to target the IDH1 mutated subsets of gliomas. New generation high-throughput genetic perturbation technologies make it possible to systematically identify the genes and pathways required for the survival and proliferation of mammalian cells. Herein, we present preliminary results from a CRISPR-dCas9 derived activation to drive the transcriptional activation of more than 23,000 coding genes in both wild type and mutant IDH1 patient-derived pediatric glioma cells. Based on an average of three viability screens per cell type, we analyzed the sgRNA library representation in the IDH1 mutated and non-mutated glioma cultures after the genome wide activation. We identified 1553 candidate genes that upon gain of function trigger the death of glioma cells harboring the IDH1 mutation. The analysis of these results further pinpoints the activation of the Cyclin E1 (CCNE1), the BCL2 Antagonist/Killer 1 (BAK1) and the Homeobox B13 (HOXB13) as the most significant synthetic lethal targets in IDH1R132H glioma cells. Interestingly, results from RNAseq showed a decreased expression of these genes in IDH1 mutated compared to non-mutated glioma cells. Thus, this viability screening aims to elucidate genes that interact with IDH1R123H and play a role in tumor cell fitness. The functional analysis of these candidate genes will allow us to uncover their contribution to the progression of IDH1 mutated gliomas.

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Nikitin, Pavel V., Guzel R. Musina, Stanislav I. Pekov, Andrey A. Kuzin, Igor A. Popov, Artem Y. Belyaev, Gregory L. Kobyakov, Dmitry Y. Usachev, Viktor N. Nikolaev, and Valentin P. Mikhailov. "Cell-Population Dynamics in Diffuse Gliomas during Gliomagenesis and Its Impact on Patient Survival." Cancers 15, no. 1 (December 26, 2022): 145. http://dx.doi.org/10.3390/cancers15010145.

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Diffuse gliomas continue to be an important problem in neuro-oncology. To solve it, studies have considered the issues of molecular pathogenesis from the intratumoral heterogeneity point. Here, we carried out a comparative dynamic analysis of the different cell populations’ content in diffuse gliomas of different molecular profiles and grades, considering the cell populations’ functional properties and the relationship with patient survival, using flow cytometry, immunofluorescence, multiparametric fluorescent in situ hybridization, polymerase chain reaction, and cultural methods. It was shown that an increase in the IDH-mutant astrocytomas and oligodendrogliomas malignancy is accompanied by an increase in stem cells’ proportion and mesenchymal cell populations’ appearance arising from oligodendrocyte-progenitor-like cells with cell plasticity and cells’ hypoxia response programs’ activation. In glioblastomas, malignancy increase is accompanied by an increase in both stem and definitive cells with mesenchymal differentiation, while proneuronal glioma stem cells are the most likely the source of mesenchymal glioma stem cells, which, in hypoxic conditions, further give rise to mesenchymal-like cells. Clinical confirmation was a mesenchymal-like cell and mesenchymal glioma stem cell number, and the hypoxic and plastic molecular programs’ activation degree had a significant effect on relapse-free and overall survival. In general, we built a multi-vector model of diffuse gliomas’ pathogenetic tracing up to the practical plane.

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Bota, Daniela A., Daniela Alexandru, Stephen T. Keir, Darell Bigner, James Vredenburgh, and Henry S. Friedman. "Proteasome inhibition with bortezomib induces cell death in GBM stem-like cells and temozolomide-resistant glioma cell lines, but stimulates GBM stem-like cells' VEGF production and angiogenesis." Journal of Neurosurgery 119, no. 6 (December 2013): 1415–23. http://dx.doi.org/10.3171/2013.7.jns1323.

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Object Recurrent malignant gliomas have inherent resistance to traditional chemotherapy. Novel therapies target specific molecular mechanisms involved in abnormal signaling and resistance to apoptosis. The proteasome is a key regulator of multiple cellular functions, and its inhibition in malignant astrocytic lines causes cell growth arrest and apoptotic cell death. The proteasome inhibitor bortezomib was reported to have very good in vitro activity against malignant glioma cell lines, with modest activity in animal models as well as in clinical trials as a single agent. In this paper, the authors describe the multiple effects of bortezomib in both in vitro and in vivo glioma models and offer a novel explanation for its seeming lack of activity. Methods Glioma stem-like cells (GSCs) were obtained from resected glioblastomas (GBMs) at surgery and expanded in culture. Stable glioma cell lines (U21 and D54) as well as temozolomide (TMZ)-resistant glioma cells derived from U251 and D54-MG were also cultured. GSCs from 2 different tumors, as well as D54 and U251 cells, were treated with bortezomib, and the effect of the drug was measured using an XTT cell viability assay. The activity of bortezomib was then determined in D54-MG and/or U251 cells using apoptosis analysis as well as caspase-3 activity and proteasome activity measurements. Human glioma xenograft models were created in nude mice by subcutaneous injection. Bevacizumab was administered via intraperitoneal injection at a dose of 5 mg/kg daily. Bortezomib was administered by intraperitoneal injection 1 hour after bevacizumab administration in doses of at a dose of 0.35 mg/kg on days 1, 4, 8, and 11 every 21 days. Tumors were measured twice weekly. Results Bortezomib induced caspase-3 activation and apoptotic cell death in stable glioma cell lines and in glioma stem-like cells (GSCs) derived from malignant tumor specimens Furthermore, TMZ-resistant glioma cell lines retained susceptibility to the proteasome inhibition. The bortezomib activity was directly proportional with the cells' baseline proteasome activity. The proteasome inhibition stimulated both hypoxia-inducible factor (HIF)–1α and vascular endothelial growth factor (VEGF) production in malignant GSCs. As such, the VEGF produced by GSCs stimulated endothelial cell growth, an effect that could be prevented by the addition of bevacizumab (VEGF antibody) to the media. Similarly, administration of bortezomib and bevacizumab to athymic mice carrying subcutaneous malignant glioma xenografts resulted in greater tumor inhibition and greater improvement in survival than administration of either drug alone. These data indicate that simultaneous proteasome inhibition and VEGF blockade offer increased benefit as a strategy for malignant glioma therapy. Conclusions The results of this study indicate that combination therapies based on bortezomib and bevacizumab might offer an increased benefit when the two agents are used in combination. These drugs have a complementary mechanism of action and therefore can be used together to treat TMZ-resistant malignant gliomas.

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Kim, Jun-Kyum, Hye-Min Jeon, Hee-Young Jeon, Se-Yeong Oh, Eun-Jung Kim, Xiong Jin, Se-Hoon Kim, Sung-Hak Kim, Xun Jin, and Hyunggee Kim. "Conversion of glioma cells to glioma stem-like cells by angiocrine factors." Biochemical and Biophysical Research Communications 496, no. 4 (February 2018): 1013–18. http://dx.doi.org/10.1016/j.bbrc.2017.02.076.

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Anand, Sumyuktha V., Alexander G. Skorput, Allan T. Gulledge, Isabella B. Fox, Damian A. Bonnin, Alison L. Young, and Matthew C. Havrda. "Abstract 905: Targeting muscarinic acetylcholine receptors in glioma stem like cells." Cancer Research 82, no. 12_Supplement (June 15, 2022): 905. http://dx.doi.org/10.1158/1538-7445.am2022-905.

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Abstract Primary gliomas arising within the brain remain the deadliest form of brain cancer and account for 78% of all malignant brain tumors. Glioblastoma patients have a 5 percent five-year survival rate and drug-resistant tumors often recur following surgical resection and treatment with radiation or chemotherapy. The cancer stem cell hypothesis suggests the presence of a subset of undifferentiated cells, namely glioma stem cells (GSCs), in the heterogenous tumor mass that are likely responsible for tumor initiation and recurrence of tumors post resection and give rise to drug resistant tumors. Determining a way to suppress these malignant characteristics and/or depleting the GSC population could improve current cancer treatments and the survival of glioma patients. Some GSCs are similar to oligodendrocyte precursor cells (OPCs), found during neural development and also residing in the adult brain. OPCs are prone to malignant transformation and believed to be a cellular origin for glioma. Recent findings indicate that the well-characterized neurotransmitter acetylcholine (ACh) maintains the primitive state of normal OPCs via muscarinic ACh receptors (mAChRs) preventing maturation and cell cycle exit. We investigated the functional characterization of ACh and mAChRs in modulating malignancy in OPC-like cells. We studied cultures of primary mouse OPC-like GSCs. We used the primary cells to culture three-dimensional tumor organoids in vitro to better represent tumor heterogeneity. We also used patient derived xenografts (PDX) of glioma to grow flank xenografts in NSG mice for an in vivo model. Publicly available data and studies in our lab show high levels of expression of CHRM3 (M3mAChR) in glioma patients and in primary OPC like GSCs. A drug screen conducted in the context of multiple sclerosis determined that benztropine (BZT), an anti muscarinic drug targeting M3mAChR, causes normal OPCs to exit the cell cycle, lose stem cell like characteristics, and differentiate. In our lab, electrophysiological studies demonstrated that activation of mAChRs in OPC-like cells from mouse and patient tumors generates rapid (< 1 second) increases in cytosolic calcium. Pharmacologic studies indicated that treatment with FDA approved anti muscarinic benztropine suppresses proliferation in cultured glioma cells. We also observed that serially passaging flank tumors treated with BZT into new host mice slowed down recurrence of new tumors. In order to determine key receptors mediating cholinergic responses in OPC-like cells we performed protein quantification, which displayed lowered phosphorylation of ERK. Electrophysiological studies are being conducted to dissect the mechanisms by which ACh evokes calcium release. These studies improve understanding of how cholinergic microenvironment influences stem-like glioma cells, providing a platform for repositioning available small molecule modifiers for treatment of glioma. Citation Format: Sumyuktha V. Anand, Alexander G. Skorput, Allan T. Gulledge, Isabella B. Fox, Damian A. Bonnin, Alison L. Young, Matthew C. Havrda. Targeting muscarinic acetylcholine receptors in glioma stem like cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 905.

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Jadus, Martin, Neil Hoa, Lisheng Ge, Yurii Kuznetsov, Alex McPherson, Andrew Cornforth, Nabil Ahmed, and Lawrence Lamb. "Gliomas display complex cell surface topographies that resist cytolytic lymphocytes but are reversed by using fascin siRNA (48.2)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 48.2. http://dx.doi.org/10.4049/jimmunol.186.supp.48.2.

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Abstract Gliomas are invasive cancers that resist all forms of attempted therapy, but immunotherapy has improved survival for some patients. We present evidence that another level of complexity may also contribute to lack of responses by the lymphocytes towards gliomas. Atomic force microscopy of four different glioma types: human U251 and rat T9 and F98 glioma cells, including freshly isolated human GBM neurosphere cultures (containing “stem cell-like cells’), revealed a complex surface topography with numerous microvilli and filopodia. These structures were not found on other cell types. Electron microscopy and immunofluorescence microscopy of glioma cells confirmed that microvilli are present. U251 cells with microvilli resisted the cytolytic actions of different human effector cells, (lymphokine-activated killer cells, γδ T cells, conventional cytolytic T lymphocytes, [CTL], and chimeric antigen receptor redirected T cells) better than their non-microvilli expressing counterparts. Killer cells released perforin which was detected within the glioma’s microvilli/ filopodia, indicating these structures can receive the cytolytic effector molecules, but cytotoxicity is suboptimal. Transfection of fascin siRNA into U251 cells prevented the microvilli from forming and allowed cytolytic cells to kill these adherent cells just as well as the non-attached glioma cells. These microvilli play multiple roles in glioma biology, such as invasion and resistance to lymphocyte-mediated killing.

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FENG, XING, QIN ZHOU, CHONG LIU, and MEI-LING TAO. "Drug screening study using glioma stem-like cells." Molecular Medicine Reports 6, no. 5 (August 20, 2012): 1117–20. http://dx.doi.org/10.3892/mmr.2012.1040.

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Persson, Anders I., and William A. Weiss. "The Side Story of Stem-like Glioma Cells." Cell Stem Cell 4, no. 3 (March 2009): 191–92. http://dx.doi.org/10.1016/j.stem.2009.02.004.

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Lichti, Cheryl F., Norelle C. Wildburger, Alexander S. Shavkunov, Ekaterina Mostovenko, Huiling Liu, Erik P. Sulman, and Carol L. Nilsson. "The proteomic landscape of glioma stem-like cells." EuPA Open Proteomics 8 (September 2015): 85–93. http://dx.doi.org/10.1016/j.euprot.2015.06.008.

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Berglar, Inka, Stephanie Hehlgans, Andrej Wehle, Caterina Roth, Christel Herold-Mende, Franz Rödel, Donat Kögel, and Benedikt Linder. "CHRDL1 Regulates Stemness in Glioma Stem-like Cells." Cells 11, no. 23 (December 3, 2022): 3917. http://dx.doi.org/10.3390/cells11233917.

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Glioblastoma (GBM) still presents as one of the most aggressive tumours in the brain, which despite enormous research efforts, remains incurable today. As many theories evolve around the persistent recurrence of this malignancy, the assumption of a small population of cells with a stem-like phenotype remains a key driver of its infiltrative nature. In this article, we research Chordin-like 1 (CHRDL1), a secreted protein, as a potential key regulator of the glioma stem-like cell (GSC) phenotype. It has been shown that CHRDL1 antagonizes the function of bone morphogenic protein 4 (BMP4), which induces GSC differentiation and, hence, reduces tumorigenicity. We, therefore, employed two previously described GSCs spheroid cultures and depleted them of CHRDL1 using the stable transduction of a CHRDL1-targeting shRNA. We show with in vitro cell-based assays (MTT, limiting dilution, and sphere formation assays), Western blots, irradiation procedures, and quantitative real-time PCR that the depletion of the secreted BMP4 antagonist CHRDL1 prominently decreases functional and molecular stemness traits resulting in enhanced radiation sensitivity. As a result, we postulate CHRDL1 as an enforcer of stemness in GSCs and find additional evidence that high CHRDL1 expression might also serve as a marker protein to determine BMP4 susceptibility.

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Rao, Aparna, Xiaoran Zhang, Christopher Deibert, Paola Sette, Paola Grandi, and Nduka Amankulor. "IDH Mutant Gliomas Escape Natural Killer Cell Immune Surveillance by Downregulation of NKG2D Ligand Expression." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 142.11. http://dx.doi.org/10.4049/jimmunol.196.supp.142.11.

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Abstract Background Diffuse gliomas are fatal primary brain tumors that are poorly immunogenic. The basis for insufficient anti-tumor immunity in diffuse gliomas is not understood. Mutations in isocitrate dehydrogenases (IDH1 and IDH2) promote diffuse glioma formation through epigenetic reprogramming of a number of genes, including immune-related genes. Here, we identify epigenetic dysregulation of natural killer (NK) cell ligand genes as significant contributors to immune escape in glioma. Methods We analyzed the TCGA database for immune gene expression patterns in IDH mutant or wild-type gliomas and identified differentially expressed immune genes. NKG2D ligands expression levels and NK cell-mediated lysis were measured in patient-derived glioma stem cells and in genetically engineered astrocytes. Finally, we assessed the impact of hypomethylating agent Decitabine as a potential NK cell sensitizing agent in IDH mutant cells. Results All IDH mutant glioma stem-like cell lines exhibited significantly lower expression of NKG2D ligands compared with IDH wild-type cells. Consistent with these findings, IDH mutant glioma cells and astrocytes were resistant to NK cell-mediated lysis. The hypomethylating agent Decitabine increased NKG2D ligand expression, and restored NK- mediated lysis of IDH mutant cells in an NKG2D-dependent manner. Conclusions IDH mutant glioma cells acquire resistance to NK cells through epigenetic silencing of NKG2D ligands ULBP1 and ULPB3. Decitabine-mediated hypomethylation restores ULBP1 and ULBP3 expression in IDH mutant glioma cells and may provide a clinically useful method to sensitize IDH mutant gliomas to NK cell-mediated immune surveillance in patients with IDH mutated diffuse gliomas.

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Mandal, Ayan S., Rafael Romero-Garcia, Michael G. Hart, and John Suckling. "Genetic, cellular, and connectomic characterization of the brain regions commonly plagued by glioma." Brain 143, no. 11 (November 2020): 3294–307. http://dx.doi.org/10.1093/brain/awaa277.

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Abstract For decades, it has been known that gliomas follow a non-random spatial distribution, appearing more often in some brain regions (e.g. the insula) compared to others (e.g. the occipital lobe). A better understanding of the localization patterns of gliomas could provide clues to the origins of these types of tumours, and consequently inform treatment targets. Following hypotheses derived from prior research into neuropsychiatric disease and cancer, gliomas may be expected to localize to brain regions characterized by functional hubness, stem-like cells, and transcription of genetic drivers of gliomagenesis. We combined neuroimaging data from 335 adult patients with high- and low-grade glioma to form a replicable tumour frequency map. Using this map, we demonstrated that glioma frequency is elevated in association cortex and correlated with multiple graph-theoretical metrics of high functional connectedness. Brain regions populated with putative cells of origin for glioma, neural stem cells and oligodendrocyte precursor cells, exhibited a high glioma frequency. Leveraging a human brain atlas of post-mortem gene expression, we found that gliomas were localized to brain regions enriched with expression of genes associated with chromatin organization and synaptic signalling. A set of glioma proto-oncogenes was enriched among the transcriptomic correlates of glioma distribution. Finally, a regression model incorporating connectomic, cellular, and genetic factors explained 58% of the variance in glioma frequency. These results add to previous literature reporting the vulnerability of hub regions to neurological disease, as well as provide support for cancer stem cell theories of glioma. Our findings illustrate how factors of diverse scale, from genetic to connectomic, can independently influence the anatomic localization of brain dysfunction.

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Richard, Seidu A., and Kuugbee D. Eugene. "The Pivotal Immunomodulatory and Anti-Inflammatory Effect of Histone-Lysine N-Methyltransferase in the Glioma Microenvironment: Its Biomarker and Therapy Potentials." Analytical Cellular Pathology 2021 (October 27, 2021): 1–15. http://dx.doi.org/10.1155/2021/4907167.

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Enhancer of zeste homolog 2 (EZH2) is a histone-lysine N-methyltransferase that encrypts a member of the Polycomb group (PcG) family. EZH2 forms a repressive chromatin structure which eventually participates in regulating the development as well as lineage propagation of stem cells and glioma progression. Posttranslational modifications are distinct approaches for the adjusted modification of EZH2 in the development of cancer. The amino acid succession of EZH2 protein makes it appropriate for covalent modifications, like phosphorylation, acetylation, O-GlcNAcylation, methylation, ubiquitination, and sumoylation. The glioma microenvironment is a dynamic component that comprises, besides glioma cells and glioma stem cells, a complex network that comprises diverse cell types like endothelial cells, astrocytes, and microglia as well as stromal components, soluble factors, and the extracellular membrane. EZH2 is well recognized as an essential modulator of cell invasion as well as metastasis in glioma. EZH2 oversecretion was implicated in the malfunction of several fundamental signaling pathways like Wnt/β-catenin signaling, Ras and NF-κB signaling, PI3K/AKT signaling, β-adrenergic receptor signaling, and bone morphogenetic protein as well as NOTCH signaling pathways. EZH2 was more secreted in glioblastoma multiforme than in low-grade gliomas as well as extremely secreted in U251 and U87 human glioma cells. Thus, the blockade of EZH2 expression in glioma could be of therapeutic value for patients with glioma. The suppression of EZH2 gene secretion was capable of reversing temozolomide resistance in patients with glioma. EZH2 is a promising therapeutic as well as prognostic biomarker for the treatment of glioma.

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Mandal, Ayan, Rafael Romero-Garcia, Michael Hart, and John Suckling. "NIMG-13. GENETIC, CELLULAR, AND CONNECTOMIC CHARACTERIZATION OF THE ADULT HUMAN BRAIN REGIONS COMMONLY PLAGUED BY GLIOMA." Neuro-Oncology 22, Supplement_2 (November 2020): ii149. http://dx.doi.org/10.1093/neuonc/noaa215.626.

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Abstract For decades, it has been known that gliomas follow a nonrandom spatial distribution, appearing more often in some brain regions (e.g. the insula) compared to others (e.g. the occipital lobe). A better understanding of the glioma localization patterns could lend clues to the origins of these types of tumors, and consequently inform treatment targets. Following hypotheses derived from prior research into neuropsychiatric disease and cancer, gliomas may be expected to localize to brain regions characterized by functional hubness, stem-like cells, and transcription of genetic drivers of gliomagenesis. We combined neuroimaging data from 335 adult patients with high- and low-grade glioma to form a replicable tumor frequency map. Using this map, we demonstrate that glioma frequency is elevated in association cortex and correlated with multiple graph-theoretical metrics of high functional connectedness. Brain regions populated with putative cells-of-origin for glioma, neural stem cells and oligodendrocyte precursor cells, exhibited a high glioma frequency. Leveraging a human brain atlas of post-mortem gene expression, we found that gliomas were localized to brain regions enriched with expression of genes associated with chromatin organization and synaptic signaling. A set of glioma proto-oncogenes was enriched among the transcriptomic correlates of glioma distribution. Finally, a regression model incorporating connectomic, cellular, and genetic factors explained 58% of the variance in glioma frequency. These results add to previous literature reporting the vulnerability of hub regions to neurological disease, as well as provide support for cancer stem cell theories of glioma. Our findings illustrate how factors of diverse scale, from genetic to connectomic, can independently influence the anatomic localization of brain dysfunction.

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Fan, Yipu, Weikang Xue, Melitta Schachner, and Weijiang Zhao. "Honokiol Eliminates Glioma/Glioblastoma Stem Cell-Like Cells Via JAK-STAT3 Signaling and Inhibits Tumor Progression by Targeting Epidermal Growth Factor Receptor." Cancers 11, no. 1 (December 26, 2018): 22. http://dx.doi.org/10.3390/cancers11010022.

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Malignant gliomas are the most aggressive forms of brain tumors; whose metastasis and recurrence contribute to high rates of morbidity and mortality. Glioma stem cell-like cells are a subpopulation of tumor-initiating cells responsible for glioma tumorigenesis, metastasis, recurrence and resistance to therapy. Epidermal growth factor receptor (EGFR) has been reported to be dysregulated in most cancers, including gliomas and its functions are closely linked to initiating tumor metastasis and a very poor prognosis. In search for compounds that may reduce the tumorigenic potential of gliomas/glioblastomas honokiol attracted our attention. Honokiol, purified from the bark of traditional Chinese herbal medicine Magnolia species, is beneficial in vitro and in animal models via a variety of pharmacological effects, including anti-inflammatory, anti-angiogenetic, anti-arrhythmic and antioxidant activities, as well as anti-proliferative and proapoptotic effects in a wide range of human cancer cells. However, its effects on glioma cells are unknown. Here, we used different concentrations of honokiol in treating U251 and U-87 MG human glioma/glioblastoma cells in cell culture. Results showed that honokiol inhibited glioma cell viability and colony formation and promoted apoptosis. It also inhibited glioma cell migration/proliferation and invasion. In addition, honokiol promoted apoptosis and reduced Bcl-2 expression, accompanied by increase in Bax expression. Honokiol reduced expression of EGFR, CD133 and Nestin. Moreover, honokiol inhibited the activation of both AKT and ERK signaling pathways, increased active caspase-3 level and reduced phosphorylation of STAT3. U-87 MG xenografts in nude mice and in immunotolerant zebrafish yolk sac showed that honokiol inhibits tumor growth and metastasis. Altogether, results indicate that honokiol reduces tumorigenic potentials, suggesting hopes for honokiol to be useful in the clinical management of glioma/glioblastoma.

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Pantazopoulou, Vasiliki, Tracy Berg, and Alexander Pietras. "TAMI-71. EFFECTS OF THE TREATED MICROENVIRONMENT ON GLIOMA CELL PROPERTIES IN AN ORGANOTYPIC BRAIN SLICE MODEL." Neuro-Oncology 23, Supplement_6 (November 2, 2021): vi213. http://dx.doi.org/10.1093/neuonc/noab196.853.

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Abstract Glioblastoma is the most aggressive primary brain tumor. Despite treatment all patients invariably recur. Treatment resistance is attributed to the presence of glioma stem-like cells. Initially thought to be a distinct and static cell population, it is becoming increasingly clear that the glioma stem-like cell phenotype represents one of many cellular states and that glioma cells show plasticity between stem-like and non-stem like states. These plastic cell states are affected by the tumor microenvironment. In our lab we have shown that irradiated and hypoxic astrocytes increase the stem-like cell properties of glioma cells. In this study, we aim to evaluate how the treated microenvironment alters glioma cell properties and use ex vivo organotypic brain slices generated from tumor bearing and tumor naïve mice to assess all aspects of the microenvironment. We first characterized organotypic brain slices cultured in different oxygen tensions. We saw that tumor-bearing slices survive for at least 14 days in culture at 21%, 5% or 1% oxygen tension (O2). Tumor cells were more viable in all culture conditions and timepoints compared to non-tumor cells. Moreover, we found that astrocytes seem to be attracted to tumor areas in both 5% and 1% O2 cultures. We then used the organotypic glioma slice culture system to address how preconditioning the microenvironment using radiation or temozolomide affects the properties of glioma cells that are seeded in these pretreated, tumor naïve slices. We saw that fluorescently labelled glioma cells seeded in treated slices can be isolated after two days of culture in the slices and can be used for downstream analyses, such as temozolomide or radiation treatment and colony formation. This study will elucidate the effect of the treated microenvironment on glioma cell properties by using the medium throughput method of organotypic slice cultures.

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Yu, Jennifer. "STEM-26. HYPOXIA REGULATES NOTCH TURNOVER IN GLIOMA STEM-LIKE CELLS." Neuro-Oncology 19, suppl_6 (November 2017): vi231. http://dx.doi.org/10.1093/neuonc/nox168.941.

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Lo Cascio, Costanza, James McNamara, Ernesto Luna Melendez, and Shwetal Mehta. "STEM-25. HDAC1 IS ESSENTIAL FOR GLIOMA STEM CELL SURVIVAL." Neuro-Oncology 21, Supplement_6 (November 2019): vi239. http://dx.doi.org/10.1093/neuonc/noz175.998.

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Abstract OLIG2 is a central nervous system-specific transcription factor that is expressed in almost all diffuse gliomas. It is also one of the key core transcription factors that can reprogram differentiated glioma cells to highly tumorigenic glioma stem-like cells (GSCs). We have previously shown that expression of OLIG2 is critical for glioma growth both in a genetically relevant mouse model as well as in patient-derived xenograft models. Our work suggests that a small molecule inhibitor of OLIG2 could serve as a highly targeted therapy for high-grade glioma; however, transcription factors are generally very difficult to target because their interactions with DNA and co-regulatory proteins involve large and complex surface area contacts. Our laboratory has shown that OLIG2 functions are regulated through interactions with distinct co-regulator proteins in normal neural stem cells. However, there are currently no reports on interactors that promote the proto-oncogenic functions of OLIG2 in malignant glioma. In this study, we employed two independent proteomics screens identify tumor-specific, druggable OLIG2 co-regulators as possible surrogate targets to suppress OLIG2 function in glioma. These screens led to the identification of a novel OLIG2 partner protein: Histone Deacetylase 1 (HDAC1). We confirmed that this interaction occurs in both murine and human glioma models. Although HDACs are ubiquitously expressed and are known to be functionally redundant, we show that ablation of HDAC1 alone significantly decreases the stemness and proliferation capacity of patient-derived GSCs in a p53-dependent manner, while having a minimal impact on normal human neural stem cells and astrocytes. Furthermore, we demonstrate that knockdown of HDAC1, in combination with ionizing radiation treatment, significantly alters the growth pattern of intracranial tumors in vivo. We demonstrate that HDAC1 function is critical for GSC growth and provide a strong rationale for targeting the OLIG2-HDAC1 interaction in malignant glioma.

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YAMAMURO, SHUN, YUTAKA OKAMOTO, EMIKO SANO, YUSHI OCHIAI, AKIYOSHI OGINO, TAKASHI OHTA, HIROYUKI HARA, et al. "Characterization of glioma stem-like cells from human glioblastomas." International Journal of Oncology 47, no. 1 (May 7, 2015): 91–96. http://dx.doi.org/10.3892/ijo.2015.2992.

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Kang, Mi-Kyung, and Soo-Kyung Kang. "Chemotherapeutic Drug Resistant Cancer Stem-like Cells of Glioma." Journal of Life Science 17, no. 8 (August 30, 2007): 1039–45. http://dx.doi.org/10.5352/jls.2007.17.8.1039.

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Nayak, Sonali, Ashorne Mahenthiran, Yongyong Yang, Mark McClendon, Barbara Mania-Farnell, Charles David James, John A. Kessler, et al. "Bone Morphogenetic Protein 4 Targeting Glioma Stem-Like Cells for Malignant Glioma Treatment: Latest Advances and Implications for Clinical Application." Cancers 12, no. 2 (February 24, 2020): 516. http://dx.doi.org/10.3390/cancers12020516.

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Malignant gliomas are heterogeneous neoplasms. Glioma stem-like cells (GSCs) are undifferentiated and self-renewing cells that develop and maintain these tumors. These cells are the main population that resist current therapies. Genomic and epigenomic analyses has identified various molecular subtypes. Bone morphogenetic protein 4 (BMP4) reduces the number of GSCs through differentiation and induction of apoptosis, thus increasing therapeutic sensitivity. However, the short half-life of BMP4 impedes its clinical application. We previously reviewed BMP4 signaling in central nervous system development and glioma tumorigenesis and its potential as a treatment target in human gliomas. Recent advances in understanding both adult and pediatric malignant gliomas highlight critical roles of BMP4 signaling pathways in the regulation of tumor biology, and indicates its potential as a therapeutic molecule. Furthermore, significant progress has been made on synthesizing BMP4 biocompatible delivery materials, which can bind to and markedly extend BMP4 half-life. Here, we review current research associated with BMP4 in brain tumors, with an emphasis on pediatric malignant gliomas. We also summarize BMP4 delivery strategies, highlighting biocompatible BMP4 binding peptide amphiphile nanostructures as promising novel delivery platforms for treatment of these devastating tumors.

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Xu, Zhong-Ye, Xiao-Qing Li, Song Chen, Yuan Cheng, Jin-Mu Deng, and Zhi-Gang Wang. "Glioma Stem-like Cells are Less Susceptible than Glioma Cells to Sonodynamic Therapy with Photofrin." Technology in Cancer Research & Treatment 11, no. 6 (December 2012): 615–23. http://dx.doi.org/10.7785/tcrt.2012.500277.

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D’Amico, Maria, and Francesca De Amicis. "Aberrant Notch signaling in gliomas: a potential landscape of actionable converging targets for combination approach in therapies resistance." Cancer Drug Resistance 5 (2022): 939–53. http://dx.doi.org/10.20517/cdr.2022.46.

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The current therapeutic protocols and prognosis of gliomas still depend on clinicopathologic and radiographic characteristics. For high-grade gliomas, the standard of care is resection followed by radiotherapy plus temozolomide chemotherapy. However, treatment resistance develops due to different mechanisms, among which is the dynamic interplay between the tumor and its microenvironment. Different signaling pathways cause the proliferation of so-called glioma stem cells, a minor cancer cell population with stem cell-like characteristics and aggressive phenotype. In the last decades, numerous studies have indicated that Notch is a crucial pathway that maintains the characteristics of resistant glioma stem cells. Data obtained from preclinical models indicate that downregulation of the Notch pathway could induce multifaceted drug sensitivity, acting on the expression of drug-transporter proteins, inducing epithelial–mesenchymal transition, and shaping the tumor microenvironment. This review provides a brief overview of the published data supporting the roles of Notch in drug resistance and demonstrates how potential novel strategies targeting Notch could become an efficacious action to improve the therapy of high-grade glioma to overcome drug resistance.

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XI, Guifa, Ashorne Mahenthiran, Benjamin Best, Sonali Nayak, Cara Smith, Mark McClendon, Barbara Mania-Farnell, et al. "EXTH-18. PEPTIDE NANO-STRUCTURES ENHANCE PEDIATRIC BRAIN TUMOR CHEMOTHERAPEUTIC EFFICACY." Neuro-Oncology 21, Supplement_6 (November 2019): vi86. http://dx.doi.org/10.1093/neuonc/noz175.352.

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Abstract Pediatric gliomas, particularly high-grade gliomas, which include diffuse intrinsic pontine gliomas (DIPGs), are among the most formidable and devastating cancers in children. These tumors remain incurable, despite many treatment approaches. We recently identified a small population of glioma cells with stem-like features in pediatric gliomas (glioma stem cells: GSCs), that may be responsible, for therapeutic resistance. Bone morphogenetic protein 4 (BMP4), essential for CNS development, increases GSC therapeutic sensitivity and is a promising adjuvant for glioma treatment. Mechanisms through which BMP4 increases therapeutic sensitivity need to be elucidated, as this can lead to identification of additional treatment targets and delivery systems for BMP4 administration in a clinical setting. Additionally, extension of BMP4 short half-life would enhance its’ clinical application. Here we show that BMP4 increases chemosensitivity by decreasing H3K4me3 at the promoter of multidrug resistant gene 1 (MDR1), resulting in decreased MDR1 expression. BMP4 appears to bring about this effect by decreasing hSETD1A, an H3K4me3 methyltransferase. Our work also demonstrates the first use of a novel sulfated glycopeptide (glyco-PA) nanostructure as a vector for BMP4 delivery. Glyco-PA markedly extended and enhanced BMP4 function, and increased chemotherapeutic anti-tumor activity against pediatric malignant glioma cells in culture. Overall, this work illuminates BMP4 effects on pediatric glioma therapeutic sensitivity through epigenetic mechanisms, and demonstrates the potential of bioactive glyco-PA nanostructures as a delivery mechanism for treating pediatric malignant gliomas and other tumors.

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Mansour, Moustafa A., Masum Rahman, Ahmad A. Ayad, Arthur E. Warrington, and Terry C. Burns. "P21 Overexpression Promotes Cell Death and Induces Senescence in Human Glioblastoma." Cancers 15, no. 4 (February 17, 2023): 1279. http://dx.doi.org/10.3390/cancers15041279.

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High-grade gliomas are the most common and aggressive adult primary brain tumors with a median survival of only 12–15 months. Current standard therapy consists of maximal safe surgical resection followed by DNA-damaging agents, such as irradiation and chemotherapy that can delay but not prevent inevitable recurrence. Some have interpreted glioma recurrence as evidence of glioma stem cells which persist in a relatively quiescent state after irradiation and chemotherapy, before the ultimate cell cycle re-entry and glioma recurrence. Conversely, latent cancer cells with a therapy-induced senescent phenotype have been shown to escape senescence, giving rise to more aggressive stem-like tumor cells than those present in the original tumor. Therefore, approaches are needed to either eliminate or keep these glioma initiating cells in a senescent state for a longer time to prolong survival. In our current study, we demonstrate that the radiation-induced cell cycle inhibitor P21 can provide a powerful route to induce cell death in short-term explants of PDXs derived from three molecularly diverse human gliomas. Additionally, cells not killed by P21 overexpression were maintained in a stable senescent state for longer than control cells. Collectively, these data suggest that P21 activation may provide an attractive therapeutic target to improve therapeutic outcomes.

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Shirakawa, Yuki, Kunimasa Ohta, Shunsuke Miyake, Ayumi Kanemaru, Akari Kuwano, Kou Yonemaru, Shota Uchino, et al. "Glioma Cells Acquire Stem-like Characters by Extrinsic Ribosome Stimuli." Cells 10, no. 11 (November 1, 2021): 2970. http://dx.doi.org/10.3390/cells10112970.

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Although glioblastoma (GBM) stem-like cells (GSCs), which retain chemo-radio resistance and recurrence, are key prognostic factors in GBM patients, the molecular mechanisms of GSC development are largely unknown. Recently, several studies revealed that extrinsic ribosome incorporation into somatic cells resulted in stem cell properties and served as a key trigger and factor for the cell reprogramming process. In this study, we aimed to investigate the mechanisms underlying GSCs development by focusing on extrinsic ribosome incorporation into GBM cells. Ribosome-induced cancer cell spheroid (RICCS) formation was significantly upregulated by ribosome incorporation. RICCS showed the stem-like cell characters (number of cell spheroid, stem cell markers, and ability for trans differentiation towards adipocytes and osteocytes). In RICCS, the phosphorylation and protein expression of ribosomal protein S6 (RPS6), an intrinsic ribosomal protein, and STAT3 phosphorylation were upregulated, and involved in the regulation of cell spheroid formation. Consistent with those results, glioma-derived extrinsic ribosome also promoted GBM-RICCS formation through intrinsic RPS6 phosphorylation. Moreover, in glioma patients, RPS6 phosphorylation was dominantly observed in high-grade glioma tissues, and predominantly upregulated in GSCs niches, such as the perinecrosis niche and perivascular niche. Those results indicate the potential biological and clinical significance of extrinsic ribosomal proteins in GSC development.

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Hede, Sanna-Maria, Inga Nazarenko, Monica Nistér, and Mikael S. Lindström. "Novel Perspectives on p53 Function in Neural Stem Cells and Brain Tumors." Journal of Oncology 2011 (2011): 1–11. http://dx.doi.org/10.1155/2011/852970.

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Malignant glioma is the most common brain tumor in adults and is associated with a very poor prognosis. Mutations in the p53 tumor suppressor gene are frequently detected in gliomas. p53 is well-known for its ability to induce cell cycle arrest, apoptosis, senescence, or differentiation following cellular stress. That the guardian of the genome also controls stem cell self-renewal and suppresses pluripotency adds a novel level of complexity to p53. Exactly how p53 works in order to prevent malignant transformation of cells in the central nervous system remains unclear, and despite being one of the most studied proteins, there is a need to acquire further knowledge about p53 in neural stem cells. Importantly, the characterization of glioma cells with stem-like properties, also known as brain tumor stem cells, has opened up for the development of novel targeted therapies. Here, we give an overview of what is currently known about p53 in brain tumors and neural stem cells. Specifically, we review the literature regarding transformation of adult neural stem cells and, we discuss how the loss of p53 and deregulation of growth factor signaling pathways, such as increased PDGF signaling, lead to brain tumor development. Reactivation of p53 in brain tumor stem cell populations in combination with current treatments for glioma should be further explored and may become a viable future therapeutic approach.

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ZHU, JIANHONG, HANDONG WANG, XIANGJUN JI, LIN ZHU, QING SUN, ZIXIANG CONG, YUAN ZHOU, HUANDONG LIU, and MENGLIANG ZHOU. "Differential Nrf2 expression between glioma stem cells and non-stem-like cells in glioblastoma." Oncology Letters 7, no. 3 (December 16, 2013): 693–98. http://dx.doi.org/10.3892/ol.2013.1760.

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Younis, Muhammad, Wang Faming, Zhao Hongyan, Tan Mengmeng, Song Hang, and Yuan Liudi. "Iguratimod encapsulated PLGA-NPs improves therapeutic outcome in glioma, glioma stem-like cells and temozolomide resistant glioma cells." Nanomedicine: Nanotechnology, Biology and Medicine 22 (November 2019): 102101. http://dx.doi.org/10.1016/j.nano.2019.102101.

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Panditharatna, Eshini, Joana G. Marques, Tingjian Wang, Maria Trissal, Ilon Liu, Li Jiang, Alexander Beck, et al. "DIPG-19. BAF COMPLEX PERTURBATION AS A NOVEL THERAPEUTIC OPPORTUNITY IN H3K27M PEDIATRIC GLIOMA." Neuro-Oncology 25, Supplement_1 (June 1, 2023): i16—i17. http://dx.doi.org/10.1093/neuonc/noad073.066.

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Abstract Epigenetic dysregulation resulting in stalled development plays a crucial role in pediatric cancer tumorigenesis. Diffuse midline gliomas (DMG) are universally fatal pediatric brain cancers refractory to standard of care treatment modalities. These malignancies are driven by heterozygous mutations in genes encoding histone 3 (H3K27M) which create an aberrant epigenetic landscape that keeps glioma cells in an undifferentiated stem-like state. Consequently, targeting epigenetic regulators to restore the epigenome and force glioma cells to exit this stem-like cell state represents a promising new therapeutic strategy for H3K27M-DMG. To interrogate for epigenetic dependencies, we performed a CRISPR/Cas9 inactivation screen in patient-derived H3K27M-DMG neurospheres using an epigenetically focused sgRNA library and identified several core components of the mammalian BAF (SWI/SNF) chromatin remodeling complex as genetic vulnerabilities. Validation assays revealed that knockout of the BAF catalytic subunit BRG1 results in decreased glioma cell proliferation and tumor growth in orthotopic mouse models. Mechanistically, genome wide localization and DNA accessibility studies combined with regulatory network analysis demonstrated that BRG1 controls the transcription factor and enhancer landscapes that maintain H3K27M-DMG cells in a cycling, oligodendrocyte precursor cell-like state. Single cell transcriptome analysis in vitro and immunofluorescence studies in vivo confirmed that genetic perturbation of this chromatin remodeler promotes progression of differentiation along the astrocytic lineage. Similarly, pharmacological suppression of BRG1 activity, using both catalytic inhibitors as well as recently developed degraders, opposes tumor cell proliferation, stimulates cell state transition, and improves overall survival of patient-derived xenograft models. Interestingly, these effects seem to be restricted to H3K27M mutant glioma, as H3 wildtype glioma cells were less sensitive to BRG1 inhibition both in vitro and in vivo. In summary, we demonstrate that the BAF complex contributes to the maintenance of glioma cells in a proliferative stem-like state and that its therapeutic inhibition has translational potential for children bearing H3K27M-DMG.

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ZHANG, SUOJUN, RUIFAN XIE, FENG WAN, FEI YE, DONGSHENG GUO, and TING LEI. "Identification of U251 glioma stem cells and their heterogeneous stem-like phenotypes." Oncology Letters 6, no. 6 (October 11, 2013): 1649–55. http://dx.doi.org/10.3892/ol.2013.1623.

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Muthukrishnan, Sree Deepthi, Riki Kawaguchi, Pooja Nair, Alvaro Alvarado, and Harley Kornblum. "Abstract B011: P300 histone acetyltransferase mediates glioma stem cell adaptive response to therapeutic stress." Cancer Research 82, no. 10_Supplement (May 15, 2022): B011. http://dx.doi.org/10.1158/1538-7445.evodyn22-b011.

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Abstract Glioma stem-like and tumor cells exhibit phenotypic plasticity in response to environmental and therapeutic stress leading to tumor recurrence, but the underlying mechanisms remain largely unknown. In this study, we employed single-cell and whole transcriptomic analyses to uncover that radiation-stress induces a dynamic shift in functional states of glioma cells allowing for acquisition of vascular endothelial-like and pericyte-like cell phenotypes. These vascular-like cells provide trophic support to promote proliferation of tumor cells, and their selective depletion results in reduced tumor growth post-treatment in vivo. Mechanistically, the acquisition of vascular-like phenotype is driven by increased chromatin accessibility and H3K27 acetylation in specific vascular gene regions allowing for their increased expression post-treatment. Blocking P300 histone acetyltransferase activity using a small molecule inhibitor C646 or gene knockdown reverses the epigenetic changes induced by radiation, inhibits the adaptive conversion of GSC into vascular-like cells, reduces tumor growth and enhances animal survival. Our findings highlight an important role for P300 in mediating adaptive response of glioma stem cells to therapeutic-stress, and opens a new therapeutic avenue for preventing glioma recurrence. Citation Format: Sree Deepthi Muthukrishnan, Riki Kawaguchi, Pooja Nair, Alvaro Alvarado, Harley Kornblum. P300 histone acetyltransferase mediates glioma stem cell adaptive response to therapeutic stress [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr B011.

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Anand, Sumyuktha V., Min K. Lee, Alexander G. Skorput, Isabella B. Fox, Alison L. Young, Brock C. Christensen, Allan Gulledge, and Matthew C. Havrda. "Abstract 5801: Inhibition of muscarinic acetylcholine receptors in glioma stem cells blocks tumor progression." Cancer Research 83, no. 7_Supplement (April 4, 2023): 5801. http://dx.doi.org/10.1158/1538-7445.am2023-5801.

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Abstract Primary gliomas arising within the brain are the deadliest form of brain cancer and account for 78% of all malignant brain tumors. Glioma patients have a 5 percent five-year survival rate and drug-resistant tumors often recur following surgical resection and treatment with radiation and/or chemotherapy. The cancer stem cell hypothesis suggests the presence of a subset of undifferentiated cells, namely glioma stem cells (GSCs), in the heterogenous tumor mass responsible for disease progression. Understanding mechanisms responsible for maintaining GSCs and developing strategies to deplete the GSC population could improve glioma treatment and prognosis. Some GSCs are similar to oligodendrocyte precursor cells (OPCs), which are observed in neural development and the adult brain. OPCs are prone to malignant transformation and are believed to be a cell of origin for glioma. Recent findings indicate that the well-characterized neurotransmitter acetylcholine (ACh) maintains the primitive state of normal OPCs via muscarinic ACh receptors (mAChRs) preventing maturation and cell cycle exit. We hypothesized that cholinergic signaling may also maintain the primitive state of OPC-like GSCs. We analyzed publicly available single nuclei RNASeq data of patient glioblastoma samples and observed high expression of CHRM3, encoding the M3 mAChR, in OPC-like cells of the proneural subtype of glioma. Studies in mouse OPC-like GSCs confirmed high levels of CHRM3 expression and demonstrated that ACh generated voltage changes and rapid (< 1 second) increases in cytosolic calcium from internal calcium stores. Exposure to a brain permeant FDA-approved anti-muscarinic drug targeting M3mAChR suppressed proliferation, evoked calcium release, and the activation of intracellular second messengers PKC and ERK. Pharmacologic inhibition of mAChRs in established patient derived glioma grafts prevented re-initiation of tumors in subsequent host animals compared with vehicle treated tumors. These studies suggest that the cholinergic microenvironment maintains GSCs in a manner similar to normal OPCs and provides a platform for repositioning available small molecule mAChR antagonists for treatment of glioma. Citation Format: Sumyuktha V. Anand, Min K. Lee, Alexander G. Skorput, Isabella B. Fox, Alison L. Young, Brock C. Christensen, Allan Gulledge, Matthew C. Havrda. Inhibition of muscarinic acetylcholine receptors in glioma stem cells blocks tumor progression. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5801.

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Gaiti, Federico, Ronan Chaligne, Dana Silverbush, Joshua Schiffman, Hannah Weisman, lloyd Kluegel, Simon Gritsch, et al. "EPCO-14. DECIPHERING DIFFERENTIATION HIERARCHIES, HERITABILITY AND PLASTICITY IN HUMAN GLIOMAS VIA SINGLE-CELL MULTI-OMICS." Neuro-Oncology 22, Supplement_2 (November 2020): ii72. http://dx.doi.org/10.1093/neuonc/noaa215.293.

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Abstract Human diffuse gliomas are incurable malignancies, where cellular state diversity fuels tumor progression and resistance to therapy. Single-cell RNA-sequencing (scRNAseq) studies recently charted the cellular states of the two major categories of human gliomas, IDH-mutant gliomas (IDH-MUT) and IDH-wildtype glioblastoma (GBM), showing that malignant cells partly recapitulate neurodevelopmental trajectories. This raises the central questions of how cell states are encoded epigenetically and whether unidirectional hierarchies or more plastic state transitions govern glioma cellular architectures. To address these questions, we generated multi-omics single-cell profiling, integrating DNA methylation (DNAme), transcriptome and genotyping of 1,728 cells from 11 GBM and IDH-MUT primary patient samples. Direct comparison of the methylomes of distinct glioma cell states revealed Polycomb repressive complex 2 (PRC2) targets DNAme as a key switch in the differentiation of malignant GBM cells. In contrast, dissecting aberrant circuits of hyper-methylation and gene expression in IDH-MUT gliomas, we observed a decoupling of the promoter methylation-expression relationship, with disruption of CTCF insulation and enhancer vulnerability which increases with cellular differentiation. To define cell state transition dynamics directly in patient samples, we generated high-resolution lineage histories of glioma cells using heritable DNAme changes, and projected the scRNAseq-derived cell states onto the lineage trees. This analysis demonstrated that cell states are heritable across malignant gliomas and, while in IDH-MUT differentiation far outpaces de-differentiation, GBM harbors a higher degree of cell state plasticity allowing reversion of GBM cells from a differentiated to a stem-like state. Overall, our work provides detailed insights into gliomagenesis, dissecting the epigenetic encoding, regulatory programs, and dynamics of the cellular states that drive human gliomas. Importantly, it also carries significant translational implication, as the high degree of de-differentiation in GBM challenges the paradigm of therapeutically targeting glioma stem-like cells to deprive tumors of their ability to regenerate.

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Costa, Barbara, Tanja Eisemann, Jens Strelau, Ingrid Spaan, Andrey Korshunov, Hai-Kun Liu, Peter Bugert, Peter Angel, and Heike Peterziel. "Intratumoral platelet aggregate formation in a murine preclinical glioma model depends on podoplanin expression on tumor cells." Blood Advances 3, no. 7 (April 4, 2019): 1092–102. http://dx.doi.org/10.1182/bloodadvances.2018015966.

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Abstract Binding of the sialomucin-like transmembrane glycoprotein podoplanin (PDPN) to the platelet receptor C-type lectin-like receptor 2 induces platelet activation and aggregation. In human high-grade gliomas, PDPN is highly expressed both in tumor cells and in tumor-associated astrocytes. In glioma patients, high expression of PDPN is associated with worse prognosis and has been shown to correlate with intratumoral platelet aggregation and an increased risk of venous thromboembolism (VTE). To functionally assess the role of PDPN in platelet aggregation in vivo, we established a syngeneic orthotopic murine glioma model in C57/Bl6 mice, based on transplantation of p53- and Pten-deficient neural stem cells. This model is characterized by the presence of intratumoral platelet aggregates and by the upregulation of PDPN both in glioma cells and in astrocytes, reflecting the characteristics of human gliomas. Deletion of PDPN either in tumor cells or in astrocytes resulted in glioma formation with similar penetrance and grade compared with control mice. Importantly, only the lack of PDPN in tumor cells, but not in astrocytes, caused a significant reduction in intratumoral platelet aggregates, whereas in vitro, both cell types have similar platelet aggregation-inducing capacities. Our results demonstrate a causative link between PDPN and platelet aggregation in gliomas and pinpoint the tumor cells as the major players in PDPN-induced platelet aggregation. Our data indicate that blocking PDPN specifically on tumor cells could represent a novel strategy to prevent platelet aggregation and thereby reduce the risk of VTE in glioma patients.

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Tiburcio, Patricia, Mary Locke, Srivydia Bhaskara, Mahesh Chandrasekharan, and Eric Huang. "STEM-25. DIFFERENTIAL REGULATION OF GLIOMA STEM-CELL MARKER NESTIN AND CD24 IN IDH-MUTANT GLIOMA." Neuro-Oncology 22, Supplement_2 (November 2020): ii201. http://dx.doi.org/10.1093/neuonc/noaa215.842.

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Abstract Heterozygous mutations in the isocitrate dehydrogenase 1 (IDH1) gene are most common in glioma, resulting in predominantly arginine to histidine substitution at codon 132. Because IDH1R132H requires a wild-type allele to produce (D)-2-hydroxyglutarate for epigenetic reprogramming, glioma cells with loss of the remaining wild-type allele (hence IDH1R132H-hemizygous) exhibit an IDH1-wild-type-like glioma phenotype and aggressive tumor growth. Although previous studies reported that transgenic IDH1R132H induced the expression of nestin—a glioma stem-cell marker, the underlying mechanism remains unclear. Furthermore, this finding seems at odds with the better outcome of IDH-mutant glioma owing to a negative association of nestin with overall survival. To gain a comprehensive understanding of glioma stem-cell marker gene regulation in IDH-mutant glioma, we compared gene expression between IDH1R132H-heterozygous and IDH1R132H-hemizygous glioma cells under adherent and spheroid growth conditions and found that glioma stem-cell marker genes, including CD44, NES, and PROM1, are generally downregulated in the spheroid growth of IDH1R132H-heterozygous cells. This result was validated in patient samples of IDH-mutant glioma compared with those of IDH-wildtype glioma, even though modest NES upregulation was observed in the adherent growth of IDH1R132H-hemizygous glioma cells. In contrast, CD24 is specifically upregulated in the spheroid growth of IDH1R132H-heterozygous cells and patient samples of IDH-mutant glioma and is apparently associated with better survival. Mechanistically, CD24 and NES expression responds differentially to alteration of (D)-2-hydroxyglutarate levels. CD24 upregulation is associated with histone and DNA demethylation as opposed to hypermethylation in those downregulated glioma stem-cell marker genes. Therefore, the better outcome of IDH-mutant glioma is orchestrated exquisitely through epigenetic reprogramming that directs bidirectional expression of glioma stem-cell marker genes.

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Parajuli, Prahlad, Mouli Mandalaparty, Chaya Brodie, Lawrence Lum, Archana Thakur, and Sandeep Mittal. "Role of Th17/IL-17 inflammatory axis in the progression of malignant gliomas (P2095)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 170.4. http://dx.doi.org/10.4049/jimmunol.190.supp.170.4.

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Abstract Recent studies on extra-cranial tumors have demonstrated a strong relationship between tumor progression and inflammation. The Th17 cells, an inflammatory T cell subtype, have been implicated with either pro- or anti-tumor activity, depending on the tumor type. Th17 cells or the cytokine IL-17 remain to be studied in malignant gliomas. The objective of our study is to explore the axis of inflammatory interactions in glioma progression by focusing on the functional significance of IL-17 and IL17 receptor (IL17R) in the tumor. Our experimental strategies include in vitro 3D culture of IL17R+ glioma cells for proliferation/differentiation and cell signaling assays and ex vivo analysis of clinical glioma tissues via multi-color flow cytometry and immunohistochemistry. We report here that: 1) There is considerable prevalence of IL-17-secreting and IL17-inducing (Th17 and CD11b+ myeloid) cells among glioma-infiltrating immune cells; 2) Th17 cells induced by glioma-derived factors, in the presence of TGF-β1, shows potential immune-suppressive phenotype; 3) IL17R is preferentially expressed in glioma stem-like cells (GSCs); 4) IL17 enhances the proliferation of GSCs in matrigel cultures; 5) IL17 induces phosphorylation of STAT3, NF-κB, and GSK-3β, while also enhancing β-catenin activity in GSCs. This study provides novel insight into inflammatory axis in glioma progression, which may have significant impact on clinical interventions in patients with malignant gliomas.

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Sharma, Vivek, Deobrat Dixit, Sadashib Ghosh, and Ellora Sen. "COX-2 regulates the proliferation of glioma stem like cells." Neurochemistry International 59, no. 5 (October 2011): 567–71. http://dx.doi.org/10.1016/j.neuint.2011.06.018.

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Brooks, Lucy J., and Simona Parrinello. "Vascular regulation of glioma stem-like cells: a balancing act." Current Opinion in Neurobiology 47 (December 2017): 8–15. http://dx.doi.org/10.1016/j.conb.2017.06.008.

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Shirakawa, Yuki, Takuichiro Hide, Michiko Yamaoka, Yuki Ito, Naofumi Ito, Kunimasa Ohta, Naoki Shinojima, Akitake Mukasa, Hideyuki Saito, and Hirofumi Jono. "Ribosomal protein S6 promotes stem‐like characters in glioma cells." Cancer Science 111, no. 6 (April 30, 2020): 2041–51. http://dx.doi.org/10.1111/cas.14399.

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Campos, Benito, Feng Wan, Mohammad Farhadi, Aurélie Ernst, Felix Zeppernick, Katrin E. Tagscherer, Rezvan Ahmadi, et al. "Differentiation Therapy Exerts Antitumor Effects on Stem-like Glioma Cells." Clinical Cancer Research 16, no. 10 (May 4, 2010): 2715–28. http://dx.doi.org/10.1158/1078-0432.ccr-09-1800.

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Figueroa, Javier, Lynette M. Phillips, Tal Shahar, Anwar Hossain, Joy Gumin, Hoon Kim, Andrew J. Bean, et al. "Exosomes from Glioma-Associated Mesenchymal Stem Cells Increase the Tumorigenicity of Glioma Stem-like Cells via Transfer of miR-1587." Cancer Research 77, no. 21 (August 30, 2017): 5808–19. http://dx.doi.org/10.1158/0008-5472.can-16-2524.

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Isokpehi, Raphael D., Katharina C. Wollenberg Valero, Barbara E. Graham, Maricica Pacurari, Jennifer N. Sims, Udensi K. Udensi, and Kenneth Ndebele. "Secondary Data Analytics of Aquaporin Expression Levels in Glioblastoma Stem-Like Cells." Cancer Informatics 14 (January 2015): CIN.S22058. http://dx.doi.org/10.4137/cin.s22058.

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Glioblastoma is the most common brain tumor in adults in which recurrence has been attributed to the presence of cancer stem cells in a hypoxic microenvironment. On the basis of tumor formation in vivo and growth type in vitro, two published microarray gene expression profiling studies grouped nine glioblastoma stem-like (GS) cell lines into one of two groups: full (GSf) or restricted (GSr) stem-like phenotypes. Aquaporin-1 (AQP1) and aquaporin-4 (AQP4) are water transport proteins that are highly expressed in primary glial-derived tumors. However, the expression levels of AQP1 and AQP4 have not been previously described in a panel of 92 glioma samples. Therefore, we designed secondary data analytics methods to determine the expression levels of AQP1 and AQP4 in GS cell lines and glioblastoma neurospheres. Our investigation also included a total of 2,566 expression levels from 28 Affymetrix microarray probe sets encoding 13 human aquaporins (AQP0–AQP12); CXCR4 (the receptor for stromal cell derived factor-1 [SDF-1], a potential glioma stem cell therapeutic target]); and PROM1 (gene encoding CD133, the widely used glioma stem cell marker). Interactive visual representation designs for integrating phenotypic features and expression levels revealed that inverse expression levels of AQP1 and AQP4 correlate with distinct phenotypes in a set of cell lines grouped into full and restricted stem-like phenotypes. Discriminant function analysis further revealed that AQP1 and AQP4 expression are better predictors for tumor formation and growth types in glioblastoma stem-like cells than are CXCR4 and PROM1. Future investigations are needed to characterize the molecular mechanisms for inverse expression levels of AQP1 and AQP4 in the glioblastoma stem-like neurospheres.

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Johnson, Kevin, Kevin Anderson, Djamel Nehar-Belaid, Frederick Varn, Amit Gujar, Elise Courtois, Paul Robson, et al. "EPCO-13. IDENTIFYING REGULATORS OF GLIOMA CELL STATE DIVERSITY AND EVOLUTION VIA JOINT SINGLE NUCLEUS RNA AND CHROMATIN ACCESSIBILITY." Neuro-Oncology 24, Supplement_7 (November 1, 2022): vii118. http://dx.doi.org/10.1093/neuonc/noac209.448.

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Abstract Glioma cellular heterogeneity and plasticity represent fundamental obstacles to effective therapies. Understanding the determinants that govern glioma cell diversity and adaptability is critical to overcoming treatment resistance. Recent single cell DNA methylation studies have demonstrated that dynamic epigenetic alterations facilitate glioma cell state shifts and stress response. However, information regarding other modes of epigenetic gene regulation, such as chromatin accessibility, and how therapy shapes cellular heterogeneity remains limited. To determine the critical regulators of glioma cell state plasticity under treatment, we profiled 36 tumors (n = 23 adult patients) with joint single nucleus RNA and ATACseq including 13 longitudinal initial – recurrent pairs that yielded a total of 79,945 cells (37,883 malignant cells). We identified chromatin peaks that were uniquely open in glioma cells (n = 14,462 peaks, FDR < 0.05) compared with tumor microenvironmental cells including neuronal, perivascular, glial, and immune populations. Among malignant cells, differentiated-like cells exhibited more recurrent regions of accessibility than stem-like cells. These populations could be further delineated by differential peak enrichment of transcription factor binding sites in the stem-like (TCF12, ASCL1), differentiated-like (SMARCC1, JUN), and proliferating stem-like (E2F4) malignant cells nominating these transcription factors as master regulators. We confirmed that these cell state-specific open chromatin peaks overlapped enhancer regions via single nucleus multiomics and bulk H3K27ac profiling in 3 patient-derived cell lines. We further demonstrated that there are cell state-specific chromatin changes at recurrence with a trend toward a more open chromatin state that was associated with coordinated transcriptional changes. Finally, we incorporated matched longitudinal whole genome sequencing data to evaluate mutational profiles and differentiate between predominantly epigenetically driven changes and epigenomic co-evolution with the genome. Together, these findings define the key epigenetic switches that shape glioma cell states and facilitate plasticity during tumor progression.

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Suresh, Rahul, Sophie Fiola, Jamie Beaulieu, and Roberto Diaz. "PATH-14. ALPHA CARDIAC ACTIN EXPRESSION IS OBSERVED IN AGGRESSIVE GLIOMA SUBTYPES AND GLIOBLASTOMA STEM CELLS." Neuro-Oncology 23, Supplement_6 (November 2, 2021): vi117. http://dx.doi.org/10.1093/neuonc/noab196.466.

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Abstract BACKGROUND Alterations in actin subunit expression have previously been observed in multiple cancers. In glioblastoma (GBM), the expression of ACTC1 has been associated with a more invasive phenotype and with shorter survival. We sought to explore the diversity of actin subunit expression across glioma subtypes and patient derived glioblastoma stem cells (GSCs). METHODS Bioinformatic analysis of multiple glioma databases was performed to profile actin subunit (ACTA1, ACTA2, ACTC1, ACTG1, ACTG2, and ACTB) mRNA levels. Expression levels were also evaluated in normal brain in comparison to liver and heart tissue. Western blot was used to analyze protein expression in GSCs, surgical tissue and human fetal astrocytes. RESULTS The primary actin subunits expressed in normal brain are beta actin (ACTB) and gamma actin (ACTG1). RNA sequencing of tissue from multiple glioma subtypes or different brain regions reveals a global increase in ACTG1 and ACTB abundance in gliomas compared to normal brain. LGG-GCIMP high and LGG-co-deleted glioma subtypes have the lowest ACTC1 expression. LGG-GCIMP low (HR 9.75, P< 0.001), LGG-mesenchymal-like (HR11.1, P< 0.001), LGG-classic-like (HR10.96, P< 0.001) subtypes are associated with ACTC1 expression. ACTC1, ACTCB, and ACTG protein expression was observed in GSCs, freshly resected GBM tissue, and human fetal astrocytes. CONCLUSIONS Gliomas have a specific pattern of actin subunit expression that differs in actin subunit type and abundance when compared to normal adult brain. Expression of ACTC1 is found in aggressive glioma subtypes and is shared by GSCs and human fetal astrocytes. Investigation into the neurodevelopmental role of ACTC1 and its contribution to oncogenic transformation in GBM is warranted.

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Gong, X., P. H. Schwartz, M. E. Linskey, and D. A. Bota. "Neural stem/progenitors and glioma stem-like cells have differential sensitivity to chemotherapy." Neurology 76, no. 13 (February 23, 2011): 1126–34. http://dx.doi.org/10.1212/wnl.0b013e318212a89f.

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Chamberlain, M. C., D. A. Bota, M. E. Linskey, and P. H. Schwartz. "Neural Stem/Progenitors and Glioma Stem-Like Cells Have Differential Sensitivity to Chemotherapy." Neurology 77, no. 22 (November 28, 2011): e135-e136. http://dx.doi.org/10.1212/wnl.0b013e318239ba7c.

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Thomas, Jonathan G., Brittany C. Parker Kerrigan, Anwar Hossain, Joy Gumin, Naoki Shinojima, Felix Nwajei, Ravesanker Ezhilarasan, Patrice Love, Erik P. Sulman, and Frederick F. Lang. "Ionizing radiation augments glioma tropism of mesenchymal stem cells." Journal of Neurosurgery 128, no. 1 (January 2018): 287–95. http://dx.doi.org/10.3171/2016.9.jns16278.

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OBJECTIVEMesenchymal stem cells (MSCs) have been shown to localize to gliomas after intravascular delivery. Because these cells home to areas of tissue injury, the authors hypothesized that the administration of ionizing radiation (IR) to tumor would enhance the tropism of MSCs to gliomas. Additionally, they sought to identify which radiation-induced factors might attract MSCs.METHODSTo assess the effect of IR on MSC migration in vitro, transwell assays using conditioned medium (CM) from an irradiated commercially available glioma cell line (U87) and from irradiated patient-derived glioma stem-like cells (GSCs; GSC7-2 and GSC11) were employed. For in vivo testing, green fluorescent protein (GFP)-labeled MSCs were injected into the carotid artery of nude mice harboring orthotopic U87, GSC7-2, or GSC17 xenografts that were treated with either 0 or 10 Gy of IR, and brain sections were quantitatively analyzed by immunofluorescence for GFP-positive cells. These GSCs were used because GSC7-2 is a weak attractor of MSCs at baseline, whereas GSC17 is a strong attractor. To determine the factors implicated in IR-induced tropism, CM from irradiated GSC7-2 and from GSC11 was assayed with a cytokine array and quantitative ELISA.RESULTSTranswell migration assays revealed statistically significant enhanced MSC migration to CM from irradiated U87, GSC7-2, and GSC11 compared with nonirradiated controls and in a dose-dependent manner. After their intravascular delivery into nude mice harboring orthotopic gliomas, MSCs engrafted more successfully in irradiated U87 (p = 0.036), compared with nonirradiated controls. IR also significantly increased the tropism of MSCs to GSC7-2 xenografts (p = 0.043), which are known to attract MSCs only poorly at baseline (weak-attractor GSCs). Ionizing radiation also increased the engraftment of MSCs in strong-attractor GSC17 xenografts, but these increases did not reach statistical significance. The chemokine CCL2 was released by GSC7-2 and GSC11 after irradiation in a dose-dependent manner and mediated in vitro transwell migration of MSCs. Immunohistochemistry revealed increased CCL2 in irradiated GSC7-2 gliomas near the site of MSC engraftment.CONCLUSIONSAdministering IR to gliomas enhances MSC localization, particularly in GSCs that attract MSCs poorly at baseline. The chemokine CCL2 appears to play a crucial role in the IR-induced tropism of MSCs to gliomas.

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Gorin, Fredric A., Nagarekha Pasupuleti, Dinesh Mahajan, and Sundeep Dugar. "Killing Glioma ‘Stem-like’ Cells via Drug-Induced Relocation of Endosomal Urokinase Proteins." Anti-Cancer Agents in Medicinal Chemistry 17, no. 1 (January 2017): 40–47. http://dx.doi.org/10.2174/1871520616666160628122901.

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High grade gliomas (HGGs) are primary CNS cancers with more than 95% of patients experiencing tumor recurrence following radiation therapy, chemotherapy, and/or an anti-angiogenic therapy. Populations of glioma ‘stem-like’ cells (GSCs) exist in both proliferative and non-proliferative states and are capable of tumor regrowth. These GSCs survive within hypoxic tumor regions and avascular tumor margins, while retaining the capability to regenerate. Successful treatment of HGGs depends on therapeutic targeting of GSCs to avert tumor regeneration. Here, we review novel intracellular mechanisms by which 3-amino-5-arylamino-6-chloro-N-(diaminomethylene) pyrazine-2-carboximide (UCD38B) and the much more potent 5’-substituted arylamino compounds (cmpd 10357) irreversibly kill GSCs utilizing caspase-independent, programmed necrotic cell death. Drug-induced relocation of a subset of endosomes to perinuclear mitochondria triggers the mitochondrial release and nuclear translocation of apoptosis inducible factor (AIF) that is followed by nuclear condensation and cancer cell demise. This drug-induced endosomal ‘mis-trafficking’ affects a subset of endosomes containing proteins belonging to the urokinase plasminogen activator system (uPAS) and guided by lipoprotein receptor protein type 1 (LRP-1). UCD38B and congeners act intracellularly and bind to intracellular urokinase plasminogen activator (uPA) to disrupt uPA binding to PAI-1 and the endosomal LRP-1 guidance protein. These small molecules are cytotoxic to persistently hypoxic and acidotic HGG cell lines and to high grade gliomas from patient derived xenografts (PDX). Immunodeficient mice with intracerebral PDX glial tumors demonstrate drug-specific, AIF- mediated necrosis after 24h of treatment. The propensity of these small molecules to kill non-proliferating and proliferating hypoxic GSCs, suggests a potential synergistic therapeutic role with radiotherapy, anti-mitotic and anti-angiogenic therapies.

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KONG, BYUNG HO, HYUN-DO SHIN, SE-HOON KIM, HYUN-SU MOK, JIN-KYOUNG SHIM, JI-HYUN LEE, HYE-JIN SHIN, et al. "Increased in vivo angiogenic effect of glioma stromal mesenchymal stem-like cells on glioma cancer stem cells from patients with glioblastoma." International Journal of Oncology 42, no. 5 (March 12, 2013): 1754–62. http://dx.doi.org/10.3892/ijo.2013.1856.

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Journal articles on the topic 'Glioma Stem-like Cells'

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