bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2023–08–27
eleven papers selected by
Oltea Sampetrean, Keio University
  1. Epigenetic neural glioblastoma enhances synaptic integration and predicts therapeutic vulnerability.
  2. Dodecafluoropentane Emulsion as a Radiosensitizer in Glioblastoma Multiforme.
  3. Sirtuin 2 inhibition modulates chromatin landscapes genome-wide to induce senescence in ATRX-deficient malignant glioma.
  4. 'Slicing' glioblastoma drivers with the Swiss cheese model.
  5. A novel EGFR variant EGFRx maintains glioblastoma stem cells through STAT5.
  6. MGMT promoter methylation predicts overall survival after chemotherapy for 1p/19q-codeleted gliomas.
  7. Targeting cholesterol homeostasis through inhibiting SREBP-2: An Achilles' heel for glioblastoma.
  8. Development of a Rabbit Human Glioblastoma Model for Testing of Endovascular Selective Intra-Arterial Infusion (ESIA) of Novel Stem Cell-Based Therapeutics.
  9. Epigenetic and molecular coordination between HDAC2 and SMAD3-SKI regulates essential brain tumour stem cell characteristics.
  10. Histological analysis of invasive glioblastoma organoids embedded in a 3D collagen matrix.
  11. Reply to "Targeting cholesterol homeostasis through inhibiting: An Achilles' heel for glioblastoma?"
  1. bioRxiv. 2023 Aug 07. pii: 2023.08.04.552017. [Epub ahead of print]
    Epigenetic neural glioblastoma enhances synaptic integration and predicts therapeutic vulnerability.
    Richard Drexler, Robin Khatri, Thomas Sauvigny, Malte Mohme, Cecile L Maire, Alice Ryba, Yahya Zghaibeh, Lasse Dührsen, Amanda Salviano-Silva, Katrin Lamszus, Manfred Westphal, Jens Gempt, Annika K Wefers, Julia Neumann, Helena Bode, Fabian Hausmann, Tobias B Huber, Stefan Bonn, Kerstin Jütten, Daniel Delev, Katharina J Weber, Patrick N Harter, Julia Onken, Peter Vajkoczy, David Capper, Benedikt Wiestler, Michael Weller, Berend Snijder, Alicia Buck, Tobias Weiss, Michael B Keough, Lijun Ni, Michelle Monje, Dana Silverbush, Volker Hovestadt, Mario L Suvà, Saritha Krishna, Shawn L Hervey-Jumper, Ulrich Schüller, Dieter H Heiland, Sonja Hänzelmann, Franz L Ricklefs.
      Neural-tumor interactions drive glioma growth as evidenced in preclinical models, but clinical validation is nascent. We present an epigenetically defined neural signature of glioblastoma that independently affects patients' survival. We use reference signatures of neural cells to deconvolve tumor DNA and classify samples into low- or high-neural tumors. High-neural glioblastomas exhibit hypomethylated CpG sites and upregulation of genes associated with synaptic integration. Single-cell transcriptomic analysis reveals high abundance of stem cell-like malignant cells classified as oligodendrocyte precursor and neural precursor cell-like in high-neural glioblastoma. High-neural glioblastoma cells engender neuron-to-glioma synapse formation in vitro and in vivo and show an unfavorable survival after xenografting. In patients, a high-neural signature associates with decreased survival as well as increased functional connectivity and can be detected via DNA analytes and brain-derived neurotrophic factor in plasma. Our study presents an epigenetically defined malignant neural signature in high-grade gliomas that is prognostically relevant.
    DOI:  https://doi.org/10.1101/2023.08.04.552017
  2. Cancer Res Commun. 2023 Aug;3(8): 1607-1614
    Dodecafluoropentane Emulsion as a Radiosensitizer in Glioblastoma Multiforme.
    Jason D Lickliter, Jeremy Ruben, Ganessan Kichenadasse, Ross Jennens, Cecelia Gzell, Ralph P Mason, Heling Zhou, Jennifer Becker, Evan Unger, Baldassarre Stea.
       Purpose: Glioblastoma multiforme (GBM) is a hypoxic tumor resistant to radiotherapy. The purpose of this study was to assess the safety and efficacy of a novel oxygen therapeutic, dodecafluoropentane emulsion (DDFPe), in chemoradiation treatment of GBM.
    Experimental Design: In this multicenter phase Ib/II dose-escalation study, patients were administered DDFPe via intravenous infusion (0.05, 0.10, or 0.17 mL/kg) while breathing supplemental oxygen prior to each 2 Gy fraction of radiotherapy (30 fractions over 6 weeks). Patients also received standard-of-care chemotherapy [temozolomide (TMZ)]. Serial MRI scans were taken to monitor disease response. Adverse events were recorded and graded. TOLD (tissue oxygenation level-dependent) contrast MRI was obtained to validate modulation of tumor hypoxia.
    Results: Eleven patients were enrolled. DDFPe combined with radiotherapy and TMZ was well tolerated in most patients. Two patients developed delayed grade 3 radiation necrosis during dose escalation, one each at 0.1 and 0.17 mL/kg of DDFPe. Subsequent patients were treated at the 0.1 mL/kg dose level. Kaplan-Meier analysis showed a median overall survival of 19.4 months and a median progression-free survival of 9.6 months, which compares favorably to historical controls. Among 6 patients evaluable for TOLD MRI, a statistically significant reduction in tumor T1 was observed after DDFPe treatment.
    Conclusions: This trial, although small, showed that the use of DDFPe as a radiosensitizer in patients with GBM was generally safe and may provide a survival benefit. This is also the first time than TOLD MRI has shown reversal of tumor hypoxia in a clinical trial in patients. The recommended dose for phase II evaluation is 0.1 mL/kg DDFPe.Trial Registration: NCT02189109.
    Significance: This study shows that DDFPe can be safely administered to patients, and it is the first-in-human study to show reversal of hypoxia in GBM as measured by TOLD MRI. This strategy is being used in a larger phase II/III trial which will hopefully show a survival benefit by adding DDFPe during the course of fractionated radiation and concurrent chemotherapy.
    DOI:  https://doi.org/10.1158/2767-9764.CRC-22-0433
  3. Neuro Oncol. 2023 Aug 25. pii: noad155. [Epub ahead of print]
    Sirtuin 2 inhibition modulates chromatin landscapes genome-wide to induce senescence in ATRX-deficient malignant glioma.
    Prit Benny Malgulwar, Carla Danussi, Sharvari Dharmaiah, William Johnson, Anand Singh, Kunal Rai, Arvind Rao, Jason T Huse.
       BACKGROUND: Functional inactivation of ATRX characterizes large subgroups of malignant gliomas in adults and children. ATRX deficiency in glioma induces widespread chromatin remodeling, driving transcriptional shifts and oncogenic phenotypes. Effective strategies to therapeutically target these broad epigenomic sequelae remain undeveloped.
    METHODS: We utilized integrated mulit-omics and the Broad Institute Connectivity Map (CMAP) to identify drug candidates that could potentially revert ATRX-deficient transcriptional changes. We then employed disease-relevant experimental models to evaluate functional phenotypes, coupling these studies with epigenomic profiling to elucidate molecular mechanism(s).
    RESULTS: CMAP analysis and transcriptional/epigenomic profiling implicated the Class III HDAC Sirtuin2 (SIRT2) as a central mediator of ATRX-deficient cellular phenotypes and a driver of unfavorable prognosis in ATRX-deficient glioma. SIRT2 inhibitors reverted Atrx-deficient transcriptional signatures in murine neuroepithelial progenitor cells (mNPCs), impaired cell migration in Atrx/ATRX-deficient mNPCs and human glioma stem cells (GSCs), and increased expression of senescence markers in glioma models. Moreover, SIRT2 inhibition impaired growth and increased senescence in ATRX-deficient GSCs in vivo. These effects were accompanied by genome-wide shifts in enhancer-associated H3K27ac and H4K16ac marks, with the latter in particular demonstrating compelling transcriptional links to SIRT2-dependent phenotypic reversals. Motif analysis of these data identified the transcription factor KLF16 as a mediator of phenotype reversal in Atrx-deficient cells upon SIRT2 inhibition.
    CONCLUSIONS: Our findings indicate that SIRT2 inhibition selectively targets ATRX-deficient gliomas for senescence through global chromatin remodeling, while demonstrating more broadly a viable approach to combat complex epigenetic rewiring in cancer.
    Keywords:  ATRX; SIRT2; astrocytoma; epigenetics; glioma
    DOI:  https://doi.org/10.1093/neuonc/noad155
  4. Trends Cancer. 2023 Aug 23. pii: S2405-8033(23)00158-9. [Epub ahead of print]
    'Slicing' glioblastoma drivers with the Swiss cheese model.
    Oriana Y Teran Pumar, Justin D Lathia, Dionysios C Watson, Defne Bayik.
      The Swiss cheese model is used to assess risks and explain accidents in a variety of industries. This model can be applied to dissect the homeostatic mechanisms whose cumulative dysregulation contributes to disease states, including cancer. Using glioblastoma (GBM) as an exemplar, we discuss how specific protumorigenic mechanisms collectively drive disease by affecting genomic integrity, epigenetic regulation, metabolic homeostasis, and antitumor immunity. We further highlight how host factors, such as hormonal differences and aging, impact this process, and the interplay between these 'system failures' that enable tumor progression and foster therapeutic resistance. Finally, we examine therapies that consider the interactions between these elements, which may comprise more effective approaches given the multifaceted protumorigenic mechanisms that drive GBM.
    Keywords:  PTEN; aging; hypoxia; interleukin-6; sex differences; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.trecan.2023.08.002
  5. Neuro Oncol. 2023 Aug 24. pii: noad153. [Epub ahead of print]
    A novel EGFR variant EGFRx maintains glioblastoma stem cells through STAT5.
    Wei Huang, Jing Li, Hongtao Zhu, Xuhui Qin, Chao Chen, Bing Wang, Jinxia Wei, Yanyang Song, Xia Lu, Zhongyu Li, Wenqing Xia, Aodi He, Lidong Cheng, Xingjiang Yu, Kai Shu, Wei Wang.
       BACKGROUND: Glioblastomas are universally lethal brain tumors containing tumor-propagating glioblastoma stem cells (GSCs). EGFR gene amplification or mutation is frequently detected in GBMs and is associated with poor prognosis. However, EGFR variants in GSCs and their role in the maintenance of GSCs and progression of GBM are unclear.
    METHODS: EGFR variants were detected through bioinformatic HISAT-StringTie-Ballgown pipeline and verified through 5' RACE, RT-PCR, ribonuclease protection, and northern blotting assays. EGFRx function was investigated through neurosphere, cell viability, intracranial xenograft and RNA-seq assays. EGFRx-STAT5 signaling was investigated through western blotting, coimmunoprecipitation, immunofluorescence, luciferase reporter, RT-PCR and CUT&Tag assays.
    RESULTS: We identified a novel EGFR variant (EGFRx), that is specifically expressed in GSCs. Unlike the EGFRvIII variant, which lacks exons 2-7, EGFRx is characterized by the absence of exons 2-14, and encodes an EGFR protein that does not possess the entire extracellular ligand-binding domain. We observed that EGFRx exhibits significant glycosylation, is required for GSC self-renewal, proliferation, and tumorigenesis, and highly active in glioblastomas compared to normal brain tissue. Mechanistically, EGFRx constitutively and specifically activates STAT5 in GSCs through spontaneous asymmetric dimerization of the kinase domain.
    CONCLUSIONS: EGFRx plays essential roles in the maintenance of the GSC phenotype through constitutive activation of STAT5 and promotes GBM progression, suggesting that EGFRx-STAT5 signaling represents a promising therapeutic target for GBM.
    Keywords:  EGFRx; GBM; STAT5; stem cells
    DOI:  https://doi.org/10.1093/neuonc/noad153
  6. Clin Cancer Res. 2023 Aug 23. pii: CCR-23-1295. [Epub ahead of print]
    MGMT promoter methylation predicts overall survival after chemotherapy for 1p/19q-codeleted gliomas.
    Connor J Kinslow, Ali I Rae, Kekoa Taparra, Prashanth Kumar, Markus D Siegelin, Jack Grinband, Brian J A Gill, Guy M McKhann, Michael B Sisti, Jeffrey N Bruce, Peter D Canoll, Fabio M Iwamoto, David P Horowitz, Lisa A Kachnic, Alfred I Neugut, James B Yu, Simon K Cheng, Tony J C Wang.
       PURPOSE: While MGMT promoter methylation (mMGMT) is predictive of response to alkylating chemotherapy and guides treatment decisions in glioblastoma, its role in grade 2 and 3 glioma remains unclear. Recent data suggests that mMGMT is prognostic of progression-free survival in 1p/19q-codeleted oligodendrogliomas, but an effect on overall survival (OS) has not been demonstrated.
    EXPERIMENTAL DESIGN: We identified patients with newly diagnosed 1p/19q-codeleted gliomas and known MGMT promoter status in the National Cancer Database from 2010-2019. Multivariable Cox proportional hazards regression modeling was used to assess the effect of mMGMT on OS after adjusting for age, sex, race, co-morbidity, grade, extent of resection, chemotherapy, and radiotherapy.
    RESULTS: We identified 1,297 eligible patients, 938 (72.3%) of whom received chemotherapy in their initial course of treatment. The MGMT promoter was methylated in 1,009 (77.8%) patients. Unmethylated MGMT (uMGMT) was associated with worse survival compared to mMGMT (70% [95%CI 64-77%] vs. 81% [95%CI 78-85%], P<.001, adjusted hazard ratio [aHR] 2.35 [95%CI 1.77-3.14]). uMGMT was associated with worse survival in patients who received chemotherapy (63% [95%CI 55-73%] vs. 80% [95%CI 76-84%], P<.001, aHR 2.61 [95%CI 1.89-3.60]) but not in patients who did not receive chemotherapy (P=.38, HR 1.31 [95%CI 0.71- 2.42]). Similar results were observed regardless of WHO grade and after single- or multiagent chemotherapy.
    CONCLUSIONS: Our study demonstrates an association between mMGMT and OS in 1p/19qcodeleted gliomas. MGMT promoter status should be considered as a stratification factor in future clinical trials of 1p/19q-codeleted gliomas that use OS as an endpoint.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-23-1295
  7. Neuro Oncol. 2023 Aug 25. pii: noad145. [Epub ahead of print]
    Targeting cholesterol homeostasis through inhibiting SREBP-2: An Achilles' heel for glioblastoma.
    Yanfei Sun, Guangjing Mu, Zhiwei Xue, Shuai Wang, Xingang Li, Mingzhi Han.
      
    DOI:  https://doi.org/10.1093/neuonc/noad145
  8. Neuro Oncol. 2023 Aug 21. pii: noad152. [Epub ahead of print]
    Development of a Rabbit Human Glioblastoma Model for Testing of Endovascular Selective Intra-Arterial Infusion (ESIA) of Novel Stem Cell-Based Therapeutics.
    Peter Kan, Visish M Srinivasan, Joy Gumin, Roberto Garcia, Stephen R Chen, Jeremiah N Johnson, Dalis E Collins, Melissa M Chen, Daniel Ledbetter, Jason Huse, Zean Aaron Evan Luna, Ariadna Robledo, Viren Vasandani, Abhijit Rao, Sanjay K Singh, Elizabeth J Shpall, Juan Fueyo, Candelaria Gomez-Manzano, Frederick F Lang.
       BACKGROUND: Endovascular selective intra-arterial (ESIA) infusion of cellular oncotherapeutics is a rapidly evolving strategy for treating glioblastoma. Evaluation of ESIA infusion requires a unique animal model. Our goal was to create a rabbit human GBM model in order to test IA infusions of cellular therapies and to test its usefulness by employing clinical-grade microcatheters and infusion methods to deliver mesenchymal stem cells loaded with an oncolytic adenovirus, Delta-24-RGD (MSC-D24).
    METHODS: Rabbits were immunosuppressed with mycophenolate mofetil, dexamethasone, and tacrolimus. They underwent stereotactic xenoimplantation of human GBM cell lines (U87, MDA-GSC-17, and MDA-GSC-8-11) into the right frontal lobe. Tumor formation was confirmed on magnetic resonance imaging, histologic, and immunohistochemistry analysis. Selective microcatheter infusion of MSC-D24 was performed via the ipsilateral internal carotid artery to assess model utility and the efficacy and safety of this approach.
    RESULTS: Twenty-five rabbits were implanted (18 with U87, 2 MDA-GSC-17, and 5 MDA-GSC-8-11). Tumors formed in 68% of rabbits (77.8% for U87, 50.0% for MDA-GSC-17, and 40.0% for MDA-GSC-8-11). On MRI, the tumors were hyperintense on T2-weighted image with variable enhancement (evidence of blood brain barrier breakdown). Histologically, tumors showed phenotypic traits of human GBM including varying levels of vascularity. ESIA infusion into the distal internal carotid artery of 2 ml of MSCs-D24 (10 7 cells) was safe in the model. Examination of post infusion specimens documented that MSCs-D24 homed to the implanted tumor at 24 hours.
    CONCLUSIONS: The intracranial immunosuppressed rabbit human GBM model allows testing of ESIA infusion of novel therapeutics (e.g., MSC-D24) in a clinically relevant fashion.
    DOI:  https://doi.org/10.1093/neuonc/noad152
  9. Nat Commun. 2023 Aug 19. 14(1): 5051
    Epigenetic and molecular coordination between HDAC2 and SMAD3-SKI regulates essential brain tumour stem cell characteristics.
    Ravinder K Bahia, Xiaoguang Hao, Rozina Hassam, Orsolya Cseh, Danielle A Bozek, H Artee Luchman, Samuel Weiss.
      Histone deacetylases are important epigenetic regulators that have been reported to play essential roles in cancer stem cell functions and are promising therapeutic targets in many cancers including glioblastoma. However, the functionally relevant roles of specific histone deacetylases, in the maintenance of key self-renewal and growth characteristics of brain tumour stem cell (BTSC) sub-populations of glioblastoma, remain to be fully resolved. Here, using pharmacological inhibition and genetic loss and gain of function approaches, we identify HDAC2 as the most relevant histone deacetylase for re-organization of chromatin accessibility resulting in maintenance of BTSC growth and self-renewal properties. Furthermore, its specific interaction with the transforming growth factor-β pathway related proteins, SMAD3 and SKI, is crucial for the maintenance of tumorigenic potential in BTSCs in vitro and in orthotopic xenograft models. Inhibition of HDAC2 activity and disruption of the coordinated mechanisms regulated by the HDAC2-SMAD3-SKI axis are thus promising therapeutic approaches for targeting BTSCs.
    DOI:  https://doi.org/10.1038/s41467-023-40776-y
  10. STAR Protoc. 2023 Aug 18. pii: S2666-1667(23)00488-4. [Epub ahead of print]4(3): 102521
    Histological analysis of invasive glioblastoma organoids embedded in a 3D collagen matrix.
    Joris Guyon, Thomas Daubon.
      Organoids are unique tools to mimic how tumors evolve in a 3D environment. Here, we present a protocol to embed spheroids invading a 3D matrix into a paraffin mold. We describe steps for preparing spheroids, collagen and agarose inclusion, and paraffinization. We then detail procedures for sectioning, staining, and visualization. This protocol allows histological identification of markers expressed in cells escaping the tumor. For complete details on the use and execution of this protocol, please refer to Guyon et al. (2022).1.
    Keywords:  Cancer; Cell Biology; Cell Culture
    DOI:  https://doi.org/10.1016/j.xpro.2023.102521
  11. Neuro Oncol. 2023 Aug 25. pii: noad146. [Epub ahead of print]
    Reply to "Targeting cholesterol homeostasis through inhibiting: An Achilles' heel for glioblastoma?"
    Danling Gu, Hao You, Jiancheng Gao, Yongping You, Jeremy N Rich, Junxia Zhang, Xiuxing Wang.
      
    DOI:  https://doi.org/10.1093/neuonc/noad146
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