bims-malgli 2023-10-15 papers

bims-malgli

Biomed News

on Biology of malignant gliomas

Issue of 2023‒10‒15
fifteen papers selected by
Oltea Sampetrean, Keio University

Vaccine shows promise in diffuse midline glioma.
Longitudinal analysis of serum-derived extracellular vesicle RNA to monitor dacomitinib treatment response in EGFR-amplified recurrent glioblastoma patients.
BRAF-targeting combination beats chemotherapy in pediatric glioma.
Systematic integration of m6A regulators and autophagy-related genes in combination with long non-coding RNAs predicts survival in glioblastoma multiforme.
Mean global DNA methylation serves as independent prognostic marker in IDH wild type glioblastoma.
H3K27M Mutant Glioma: Disease Definition and Biological Underpinnings.
Single-cell mechanical analysis reveals viscoelastic similarities between normal and neoplastic brain cells.
Rewiring of the promoter-enhancer interactome and regulatory landscape in glioblastoma orchestrates gene expression underlying neurogliomal synaptic communication.
Preclinical glioma models in neuro-oncology: enhancing translational research.
Supplementation with a high-glucose drink stimulates anti-tumor immune responses to glioblastoma via gut microbiota modulation.
Targeting of endothelial cells in brain tumours.
Dabrafenib-trametinib moves to the first line in low-grade glioma.
Sex-related incidence and survival differences in pediatric high-grade glioma subtypes: A population-based cohort study.
Combined immunotherapy improves outcome for replication repair deficient (RRD) high-grade glioma failing anti-PD1 monotherapy: A report from the International RRD Consortium.
Neuropathologist-level integrated classification of adult-type diffuse gliomas using deep learning from whole-slide pathological images.

Nat Rev Neurol. 2023 Oct 09.

Vaccine shows promise in diffuse midline glioma.

Heather Wood.

DOI: https://doi.org/10.1038/s41582-023-00888-x
Neurooncol Adv. 2023 Jan-Dec;5(1):5(1): vdad104

Longitudinal analysis of serum-derived extracellular vesicle RNA to monitor dacomitinib treatment response in EGFR-amplified recurrent glioblastoma patients.

Anudeep Yekula, Tiffaney Hsia, Robert R Kitchen, Sudipto K Chakrabortty, Wei Yu, Syeda M Batool, Brian Lewis, Antoni J Szeglowski, Ralph Weissleder, Hakho Lee, Andrew S Chi, Tracy Batchelor, Bob S Carter, Xandra O Breakefield, Johan Skog, Leonora Balaj.

  Background: Glioblastoma (GBM) is a highly aggressive and invasive brain tumor associated with high patient mortality. A large fraction of GBM tumors have been identified as epidermal growth factor receptor (EGFR) amplified and ~50% also are EGFRvIII mutant positive. In a previously reported multicenter phase II study, we have described the response of recurrent GBM (rGBM) patients to dacomitinib, an EGFR tyrosine kinase inhibitor (TKI). As a continuation of that report, we leverage the tumor cargo-encapsulating extracellular vesicles (EVs) and explore their genetic composition as carriers of tumor biomarker.Methods: Serum samples were longitudinally collected from EGFR-amplified rGBM patients who clinically benefitted from dacomitinib therapy (responders) and those who did not (nonresponders), as well as from a healthy cohort of individuals. The serum EV transcriptome was evaluated to map the RNA biotype distribution and distinguish GBM disease.
Results: Using long RNA sequencing, we show enriched detection of over 10 000 coding RNAs from serum EVs. The EV transcriptome yielded a unique signature that facilitates differentiation of GBM patients from healthy donors. Further analysis revealed genetic enrichment that enables stratification of responders from nonresponders prior to dacomitinib treatment as well as following administration.
Conclusion: This study demonstrates that genetic composition analysis of serum EVs may aid in therapeutic stratification to identify patients with dacomitinib-responsive GBM.

Keywords:  EGFR; RNA sequencing; dacomitinib; glioblastoma; liquid biopsy

DOI:  https://doi.org/10.1093/noajnl/vdad104
Nat Med. 2023 Oct 09.

BRAF-targeting combination beats chemotherapy in pediatric glioma.

Karen O'Leary.



Keywords:  Clinical trials; Paediatrics; Targeted therapies

DOI:  https://doi.org/10.1038/d41591-023-00089-5
Sci Rep. 2023 Oct 11. 13(1): 17232

Systematic integration of m6A regulators and autophagy-related genes in combination with long non-coding RNAs predicts survival in glioblastoma multiforme.

Amit Sharma, Yulu Wang, Fangfang Ge, Peng Chen, Tikam Chand Dakal, Maria Stella Carro, Ingo G H Schmidt-Wolf, Jarek Maciaczyk.

Glioblastoma multiforme (GBM) is probably the only tumor in which a unique epigenetic alteration, namely methylation of the MGMT gene, possesses direct clinical relevance. Now with the emergence of aberrant N6 methyladenosine (m6A) modifications (the most common epigenetic modification of mRNA, closely linked to the autophagy process) in cancer, the epi-transcriptomic landscape of GBM pathobiology has been expanded. Considering this, herein, we systematically analyzed m6A regulators, assessed their correlation with autophagy-related genes (ATG), and established a long non-coding RNAs (lncRNA)-dependent prognostic signature (m6A-autophagy-lncRNAs) for GBM. Our analysis identified a novel signature of five long non-coding RNAs (lncRNAs: ITGA6-AS1, AC124248.1, NFYC-AS1, AC025171.1, and AC005229.3) associated with survival of GBM patients, and four among them clearly showed cancer-associated potential. We further validated and confirmed the altered expression of two lncRNAs (AC124248.1, AC005229.3) in GBM associated clinical samples using RT-PCR. Concerning the prognostic ability, the obtained signature determined high-/low-risk groups in GBM patients and showed sensitivity to anticancer drugs. Collectively, the m6A-autophagy-lncRNAs signature presented in the study is clinically relevant and is the first attempt to systematically predict the potential interaction between the three key determinants (m6A, autophagy, lncRNA) in cancer, particularly in GBM.

DOI: https://doi.org/10.1038/s41598-023-44087-6
Neuro Oncol. 2023 Oct 11. pii: noad197. [Epub ahead of print]

Mean global DNA methylation serves as independent prognostic marker in IDH wild type glioblastoma.

Alicia Eckhardt, Richard Drexler, Melanie Schoof, Nina Struve, David Capper, Claudius Jelgersma, Julia Onken, Patrick N Harter, Katharina J Weber, Iris Divé, Kai Rothkamm, Konstantin Hoffer, Lukas Klumpp, Katrin Ganser, Cordula Petersen, Franz Ricklefs, Malte Kriegs, Ulrich Schüller.

  BACKGROUND: The IDH wild type glioblastoma (GBM) patients have a devastating prognosis. Here, we analyzed the potential prognostic value of global DNA methylation of the tumors.METHODS: DNA methylation of 492 primary samples and 31 relapsed samples, each treated with combination therapy, and of 148 primary samples treated with radiation alone were compared with patient survival. We determined the mean methylation values and estimated the immune cell infiltration from the methylation data. Moreover, the mean global DNA methylation of 23 GBM cell lines was profiled and correlated to their cellular radiosensitivity as measured by colony formation assay.
RESULTS: High mean DNA methylation levels correlated with improved survival, which was independent from known risk factors (MGMT promoter methylation, age, extent of resection; p=0.009) and methylation subgroups. Notably, this correlation was also independent of immune cell infiltration since higher number of immune cells indeed was associated with significantly better OS but lower mean methylation. Radiosensitive GBM cell lines had a significantly higher mean methylation than resistant lines (p=0.007), and improved OS of patients treated with radiotherapy alone was also associated with higher DNA methylation (p=0.002). Furthermore, specimens of relapsed GBM revealed a significantly lower mean DNA methylation compared to the matching primary tumor samples (p=0.041).
CONCLUSIONS: Our results indicate that mean global DNA methylation is independently associated with outcome in glioblastoma. The data also suggest that a higher DNA methylation is associated with better radiotherapy response and less aggressive phenotype, both of which presumably contribute to the observed correlation with OS.

Keywords:  DNA methylation; glioblastoma; overall survival; radiotherapy response

DOI:  https://doi.org/10.1093/neuonc/noad197
Neuro Oncol. 2023 Oct 11. pii: noad164. [Epub ahead of print]

H3K27M Mutant Glioma: Disease Definition and Biological Underpinnings.

Amanda M Saratsis, Truman Knowles, Antonela Petrovic, Javad Nazarian.

  High-grade glioma (HGG) is the most common cause of cancer death in children, and the most common primary central nervous system (CNS) tumor in adults. While pediatric HGG was once thought to be biologically similar to the adult form of disease, research has shown these malignancies to be significantly molecularly distinct, necessitating distinct approaches to their clinical management. However, emerging data have shown shared molecular events in pediatric and adult HGG including the histone H3K27M mutation. This somatic missense mutation occurs in genes encoding one of two isoforms of the Histone H3 protein, H3F3A (H3.3) or HIST1H3B (H3.1), and is detected in up to 80% of pediatric diffuse midline gliomas and in up to 60% of adult diffuse gliomas. Importantly, the H3K27M mutation is associated with poorer overall survival and response to therapy compared to patients with H3 wild-type tumors. Here, we review the clinical features and biological underpinnings of pediatric and adult H3K27M mutant glioma, offering a groundwork for understanding current research and clinical approaches for the care of patients suffering with this challenging disease.

Keywords:  H3K27M; epigenetics; glioma; histone; mutant

DOI:  https://doi.org/10.1093/neuonc/noad164
bioRxiv. 2023 Sep 25. pii: 2023.09.23.559055. [Epub ahead of print]

Single-cell mechanical analysis reveals viscoelastic similarities between normal and neoplastic brain cells.

Killian Onwudiwe, Julian Najera, Luke Holen, Alice A Burchett, Dorielis Rodriguez, Maksym Zarodniuk, Saeed Siri, Meenal Datta.

Understanding cancer cell mechanics allows for the identification of novel disease mechanisms, diagnostic biomarkers, and targeted therapies. In this study, we utilized our previously established fluid shear stress assay to investigate and compare the viscoelastic properties of normal immortalized human astrocytes (IHAs) and invasive human glioblastoma (GBM) cells when subjected to physiological levels of shear stress that are present in the brain microenvironment. We used a parallel-flow microfluidic shear system and a camera-coupled optical microscope to expose single cells to fluid shear stress and monitor the resulting deformation in real-time, respectively. From the video-rate imaging, we fed cell deformation information from digital image correlation into a three-parameter generalized Maxwell model to quantify the nuclear and cytoplasmic viscoelastic properties of single cells. We further quantified actin cytoskeleton density and alignment in IHAs and GBM cells via immunofluorescence microscopy and image analysis techniques. Results from our study show that contrary to the behavior of many extracranial cells, normal and cancerous brain cells do not exhibit significant differences in their viscoelastic behavior. Moreover, we also found that the viscoelastic properties of the nucleus and cytoplasm as well as the actin cytoskeletal densities of both brain cell types are similar. Our work suggests that malignant GBM cells exhibit unique mechanical behaviors not seen in other cancer cell types. These results warrant future study to elucidate the distinct biophysical characteristics of the brain and reveal novel mechanical attributes of GBM and other primary brain tumors.

DOI: https://doi.org/10.1101/2023.09.23.559055
Nat Commun. 2023 Oct 13. 14(1): 6446

Rewiring of the promoter-enhancer interactome and regulatory landscape in glioblastoma orchestrates gene expression underlying neurogliomal synaptic communication.

Chaitali Chakraborty, Itzel Nissen, Craig A Vincent, Anna-Carin Hägglund, Andreas Hörnblad, Silvia Remeseiro.

Chromatin organization controls transcription by modulating 3D-interactions between enhancers and promoters in the nucleus. Alterations in epigenetic states and 3D-chromatin organization result in gene expression changes contributing to cancer. Here, we map the promoter-enhancer interactome and regulatory landscape of glioblastoma, the most aggressive primary brain tumour. Our data reveals profound rewiring of promoter-enhancer interactions, chromatin accessibility and redistribution of histone marks in glioblastoma. This leads to loss of long-range regulatory interactions and overall activation of promoters, which orchestrate changes in the expression of genes associated to glutamatergic synapses, axon guidance, axonogenesis and chromatin remodelling. SMAD3 and PITX1 emerge as major transcription factors controlling genes related to synapse organization and axon guidance. Inhibition of SMAD3 and neuronal activity stimulation cooperate to promote proliferation of glioblastoma cells in co-culture with glutamatergic neurons, and in mice bearing patient-derived xenografts. Our findings provide mechanistic insight into the regulatory networks that mediate neurogliomal synaptic communication.

DOI: https://doi.org/10.1038/s41467-023-41919-x
Curr Opin Oncol. 2023 Nov 01. 35(6): 536-542

Preclinical glioma models in neuro-oncology: enhancing translational research.

Serena Barachini, Mariangela Morelli, Orazio Santo Santonocito, Chiara Maria Mazzanti.

PURPOSE OF REVIEW: Gliomas represent approximately 25% of all primary brain and other central nervous system (CNS) tumors and 81% of malignant tumors. Unfortunately, standard treatment approaches for most CNS cancers have shown limited improvement in patient survival rates.RECENT FINDINGS: The current drug development process has been plagued by high failure rates, leading to a shift towards human disease models in biomedical research. Unfortunately, suitable preclinical models for brain tumors have been lacking, hampering our understanding of tumor initiation processes and the discovery of effective treatments. In this review, we will explore the diverse preclinical models employed in neuro-oncology research and their contributions to translational science.
SUMMARY: By utilizing a combination of these preclinical models and fostering interdisciplinary collaborations, researchers can deepen their understanding of glioma brain tumors and develop novel therapeutic strategies to combat these devastating diseases. These models offer promising prospects for personalized and efficacious treatments for these challenging malignancies. Although it is unrealistic to fully replicate the complexity of the human body in vitro, the ultimate goal should be to achieve the closest possible resemblance to the clinical context.

DOI: https://doi.org/10.1097/CCO.0000000000000997
Cell Rep. 2023 Oct 06. pii: S2211-1247(23)01232-9. [Epub ahead of print]42(10): 113220

Supplementation with a high-glucose drink stimulates anti-tumor immune responses to glioblastoma via gut microbiota modulation.

Jaeho Kim, Yumin Kim, Jeongwoo La, Won Hyung Park, Hyun-Jin Kim, Sang Hee Park, Keun Bon Ku, Byeong Hoon Kang, Juhee Lim, Myoung Seung Kwon, Heung Kyu Lee.

  A high-sugar diet induces lifestyle-associated metabolic diseases, such as obesity and diabetes, which may underlie the pro-tumor effects of a high-sugar diet. We supply GL261 syngeneic glioblastoma (GBM) mice with a short-term high-glucose drink (HGD) and find an increased survival rate with no evidence of metabolic disease. Modulation of the gut microbiota through HGD supplementation is critical for enhancing the anti-tumor immune response. Single-cell RNA sequencing shows that gut microbiota modulation by HGD supplementation increases the T cell-mediated anti-tumor immune response in GBM mice. We find that the cytotoxic CD4+ T cell population in GBM is increased due to synergy with anti-programmed cell death protein 1 (anti-PD-1) immune checkpoint inhibitors, but this effect depends upon HGD supplementation. Thus, we determine that HGD supplementation enhances anti-tumor immune responses in GBM mice through gut microbiota modulation and suggest that the role of HGD supplementation in GBM should be re-examined.

Keywords:  CP: Cancer; CP: Immunology; anti-tumor immune response; glioblastoma; gut microbiota; high-glucose drink; immune checkpoint inhibitors

DOI:  https://doi.org/10.1016/j.celrep.2023.113220
Clin Transl Med. 2023 Oct;13(10): e1433

Targeting of endothelial cells in brain tumours.

Wenzhe Duan, Shengkai Xia, Mengyi Tang, Manqing Lin, Wenwen Liu, Qi Wang.

  BACKGROUND: Aggressive brain tumours, whether primary gliomas or secondary metastases, are characterised by hypervascularisation and are fatal. Recent research has emphasised the crucial involvement of endothelial cells (ECs) in all brain tumour genesis and development events, with various patterns and underlying mechanisms identified.MAIN BODY: Here, we highlight recent advances in knowledge about the contributions of ECs to brain tumour development, providing a comprehensive summary including descriptions of interactions between ECs and tumour cells, the heterogeneity of ECs and new models for research on ECs in brain malignancies. We also discuss prospects for EC targeting in novel therapeutic approaches.
CONCLUSION: Interventions targeting ECs, as an adjunct to other therapies (e.g. immunotherapies, molecular-targeted therapies), have shown promising clinical efficacy due to the high degree of vascularisation in brain tumours. Developing precise strategies to target tumour-associated vessels based on the heterogeneity of ECs is expected to improve anti-vascular efficacy.

Keywords:  angiogenesis; brain metastasis; brain tumours; endothelial cells; glioblastoma

DOI:  https://doi.org/10.1002/ctm2.1433
Nat Rev Clin Oncol. 2023 Oct 10.

Dabrafenib-trametinib moves to the first line in low-grade glioma.

Diana Romero.

DOI: https://doi.org/10.1038/s41571-023-00829-z
iScience. 2023 Oct 20. 26(10): 107957

Sex-related incidence and survival differences in pediatric high-grade glioma subtypes: A population-based cohort study.

Raoull Hoogendijk, Jasper van der Lugt, Josh Baugh, Cassie Kline, Mariette Kranendonk, Eelco Hoving, Leontien Kremer, Pieter Wesseling, Henrike Karim-Kos, Dannis van Vuurden.

  Not much is known on sex differences in incidence, survival, and treatment characteristics for midline and hemispheric pHGGs. This population-based study confirms previously reported study results that found worse survival outcomes for malignant diffuse gliomas in girls in the age group 0-9 years. Additionally, in our study we pinpoint this difference to girls with midline pHGGs aged 0-4 years. We provide insight in the possible underlying mechanisms contributing to sex survival differences in pHGG patients. With first line treatment having no impact on the higher risk of dying for girls, but age and tumor characteristics having a neutralizing effect. The results of this population-based study serve as a basis for future pre-clinical and clinical studies to further unravel the underlying mechanisms responsible for the survival gap between sexes in midline pHGG.

Keywords:  Cancer; Pediatrics; Population; Public health

DOI:  https://doi.org/10.1016/j.isci.2023.107957
Cancer Discov. 2023 Oct 12.

Combined immunotherapy improves outcome for replication repair deficient (RRD) high-grade glioma failing anti-PD1 monotherapy: A report from the International RRD Consortium.

Anirban Das, Nicholas R Fernandez, Adrian Levine, Vanessa Bianchi, Lucie K Stengs, Jiil Chung, Logine Negm, Jose Rafael Dimayacyac, Yuan Chang, Liana Nobre, Ayse B Ercan, Santiago Sanchez-Ramirez, Sumedha Sudhaman, Melissa Edwards, Valerie Larouche, David Samuel, An Van Damme, David Gass, David S Ziegler, Stefan S Bielack, Carl Koschmann, Shayna Zelcer, Michal Yalon-Oren, Gadi Abede Campino, Tomasz Sarosiek, Kim E Nichols, Rebecca Loret De Mola, Kevin Bielamowicz, Magnus Sabel, Charlotta A Frojd, Matthew D Wood, Jason M Glover, Yi-Yen Lee, Magimairajan Vanan, Jenny K Adamski, Sebastien Perreault, Omar Chamdine, Magnus Aasved Hjort, Michal Zapotocky, Fernando Carceller, Erin Wright, Ivana Fedorakova, Alexander Lossos, Ryuma Tanaka, Michael Osborn, Deborah T Blumenthal, Melyssa Aronson, Ute Bartels, Annie Huang, Vijay Ramaswamy, David Malkin, Adam Shlien, Anita Villani, Peter B Dirks, Trevor J Pugh, Gad Getz, Yosef E Maruvka, Derek S Tsang, Birgit Ertl-Wagner, Cynthia Hawkins, Eric Bouffet, Daniel A Morgenstern, Uri Tabori.

Immune-checkpoint inhibition (ICI) is effective for replication-repair deficient, high-grade gliomas (RRD-HGG). Clinical/biologic impact of immune-directed approaches after failing ICI-monotherapy are unknown. We performed an international study on 75 patients treated with anti-PD1; 20 are progression-free (median follow-up: 3.7-years). After 2nd-progression/recurrence (n=55), continuing ICI-based salvage prolonged survival to 11.6-months (n=38; p<0.001), particularly for those with extreme mutation burden (p=0.03). Delayed, sustained responses were observed, associated with changes in mutational spectra and immune-microenvironment. Response to re-irradiation was explained by an absence of deleterious post-radiation indel signatures (ID8). Increased CTLA4-expression over time, and subsequent CTLA4-inhibition resulted in response/stable disease in 75%. RAS-MAPK-pathway inhibition led to reinvigoration of peripheral immune and radiological responses. Local (flare) and systemic immune adverse events were frequent (biallelic mismatch-repair deficiency > Lynch syndrome). We provide mechanistic rationale for the sustained benefit in RRD-HGG from immune-directed/ synergistic salvage therapies. Future approaches need to be tailored to patient and tumor biology.

DOI: https://doi.org/10.1158/2159-8290.CD-23-0559
Nat Commun. 2023 Oct 11. 14(1): 6359

Neuropathologist-level integrated classification of adult-type diffuse gliomas using deep learning from whole-slide pathological images.

Weiwei Wang, Yuanshen Zhao, Lianghong Teng, Jing Yan, Yang Guo, Yuning Qiu, Yuchen Ji, Bin Yu, Dongling Pei, Wenchao Duan, Minkai Wang, Li Wang, Jingxian Duan, Qiuchang Sun, Shengnan Wang, Huanli Duan, Chen Sun, Yu Guo, Lin Luo, Zhixuan Guo, Fangzhan Guan, Zilong Wang, Aoqi Xing, Zhongyi Liu, Hongyan Zhang, Li Cui, Lan Zhang, Guozhong Jiang, Dongming Yan, Xianzhi Liu, Hairong Zheng, Dong Liang, Wencai Li, Zhi-Cheng Li, Zhenyu Zhang.

Current diagnosis of glioma types requires combining both histological features and molecular characteristics, which is an expensive and time-consuming procedure. Determining the tumor types directly from whole-slide images (WSIs) is of great value for glioma diagnosis. This study presents an integrated diagnosis model for automatic classification of diffuse gliomas from annotation-free standard WSIs. Our model is developed on a training cohort (n = 1362) and a validation cohort (n = 340), and tested on an internal testing cohort (n = 289) and two external cohorts (n = 305 and 328, respectively). The model can learn imaging features containing both pathological morphology and underlying biological clues to achieve the integrated diagnosis. Our model achieves high performance with area under receiver operator curve all above 0.90 in classifying major tumor types, in identifying tumor grades within type, and especially in distinguishing tumor genotypes with shared histological features. This integrated diagnosis model has the potential to be used in clinical scenarios for automated and unbiased classification of adult-type diffuse gliomas.

DOI: https://doi.org/10.1038/s41467-023-41195-9