bims-malgli 2025-03-09 papers

bims-malgli

Biomed News

on Biology of malignant gliomas

Issue of 2025–03–09
nine papers selected by
Oltea Sampetrean, Keio University

Visualizing the endothelial glycocalyx in human glioma vasculature.
Deuterium metabolic imaging phenotypes mouse glioblastoma heterogeneity through glucose turnover kinetics.
A pathogenic subpopulation of human glioma associated macrophages linked to glioma progression.
Longitudinal profiling of IDH-mutant astrocytomas reveals acquired RAS-MAPK pathway mutations associated with inferior survival.
Three-dimensional regulatory hubs support oncogenic programs in glioblastoma.
Applications of Artificial Intelligence and Advanced Imaging in Pediatric Diffuse Midline Glioma.
Personalized tumor-specific amplified DNA junctions in peripheral blood of patients with glioblastoma.
ARHGAP12 and ARHGAP29 exert distinct regulatory effects on switching between two cell morphological states through GSK-3 activity.
Targeting the SP/KLF Transcriptional Regulatory Network Synergizes with HDAC Inhibition to Impede Progression of H3K27M Diffuse Intrinsic Pontine Glioma.

Brain Tumor Pathol. 2025 Mar 04.

Visualizing the endothelial glycocalyx in human glioma vasculature.

Kazufumi Ohmura, Hiroyuki Tomita, Hideshi Okada, Noriyuki Nakayama, Naoyuki Ohe, Tsuyoshi Izumo, Akira Hara.

  Gliomas are the most common primary brain tumors in adults. However, glioblastoma is especially difficult to treat despite advancements in treatment. Therefore, new and more effective treatments are needed. The endothelial glycocalyx covers the luminal surface of the endothelium and plays an important role in vascular homeostasis. Tumor blood vessels normally have increased permeability, but some of them mimic normal cerebral blood vessels constituting the blood-brain barrier and retain drug-barrier function. Therefore, brain tumor vessels are considered to constitute the blood-tumor barrier. There are few reports on the endothelial glycocalyx in human brain tumor vessels. We aimed to visualize the endothelial glycocalyx in human brain tumor vessels and evaluate its microstructural differences in glioma vessels and normal capillaries. Surgical specimens from patients with glioma who underwent tumor resection at our institution were evaluated. We visualized the microstructures of the brain tumor vessels in human glioma specimens using electron microscopy with lanthanum nitrate. The endothelial glycocalyx was identified in the human glioma vasculature and its microstructure varied between the tumor margin and core. These variations may influence tumor angiogenesis and vascular remodeling, contributing to advancements in targeted therapies and diagnostics for human gliomas.

Keywords:  Blood–brain barrier; Blood–tumor barrier; Electron microscopy; Endothelial glycocalyx; Glioblastoma; Glioma

DOI:  https://doi.org/10.1007/s10014-025-00498-z
Elife. 2025 Mar 04. pii: RP100570. [Epub ahead of print]13

Deuterium metabolic imaging phenotypes mouse glioblastoma heterogeneity through glucose turnover kinetics.

Rui Vasco Simoes, Rafael Neto Henriques, Jonas L Olesen, Beatriz M Cardoso, Francisca F Fernandes, Mariana A V Monteiro, Sune N Jespersen, Tânia Carvalho, Noam Shemesh.

  Glioblastomas are aggressive brain tumors with dismal prognosis. One of the main bottlenecks for developing more effective therapies for glioblastoma stems from their histologic and molecular heterogeneity, leading to distinct tumor microenvironments and disease phenotypes. Effectively characterizing these features would improve the clinical management of glioblastoma. Glucose flux rates through glycolysis and mitochondrial oxidation have been recently shown to quantitatively depict glioblastoma proliferation in mouse models (GL261 and CT2A tumors) using dynamic glucose-enhanced (DGE) deuterium spectroscopy. However, the spatial features of tumor microenvironment phenotypes remain hitherto unresolved. Here, we develop a DGE Deuterium Metabolic Imaging (DMI) approach for profiling tumor microenvironments through glucose conversion kinetics. Using a multimodal combination of tumor mouse models, novel strategies for spectroscopic imaging and noise attenuation, and histopathological correlations, we show that tumor lactate turnover mirrors phenotype differences between GL261 and CT2A mouse glioblastoma, whereas recycling of the peritumoral glutamate-glutamine pool is a potential marker of invasion capacity in pooled cohorts, linked to secondary brain lesions. These findings were validated by histopathological characterization of each tumor, including cell density and proliferation, peritumoral invasion and distant migration, and immune cell infiltration. Our study bodes well for precision neuro-oncology, highlighting the importance of mapping glucose flux rates to better understand the metabolic heterogeneity of glioblastoma and its links to disease phenotypes.

Keywords:  cancer biology; deuterium metabolic imaging; glioblastoma; glycolysis; kinetic modeling; mitochondrial metabolism; mouse

DOI:  https://doi.org/10.7554/eLife.100570
bioRxiv. 2025 Feb 17. pii: 2025.02.12.637857. [Epub ahead of print]

A pathogenic subpopulation of human glioma associated macrophages linked to glioma progression.

Kenny Kwok Hei Yu, Zaki Abou-Mrad, Kristof Törkenczy, Isabell Schulze, Jennifer Gantchev, Gerard Baquer, Kelsey Hopland, Evan D Bander, Umberto Tosi, Cameron Brennan, Nelson S Moss, Pierre-Jacques Hamard, Richard Koche, Caleb Lareau, Nathalie Y R Agar, Taha Merghoub, Viviane Tabar.

Malignant gliomas follow two distinct natural histories: de novo high grade tumors such as glioblastoma, or lower grade tumors with a propensity to transform into high grade disease. Despite differences in tumor genotype, both entities converge on a common histologically aggressive phenotype, and the basis for this progression is unknown. Glioma associated macrophages (GAM) have been implicated in this process, however GAMs are ontologically and transcriptionally diverse, rendering isolation of pathogenic subpopulations challenging. Since macrophage contextual gene programs are orchestrated by transcription factors acting on cis -acting promoters and enhancers in gene regulatory networks (GRN), we hypothesized that functional populations of GAMs can be resolved through GRN inference. Here we show via parallel single cell RNA and ATAC sequencing that a subpopulation of human GAMs can be defined by a GRN centered around the Activator Protein-1 transcription factor FOSL2 preferentially enriched in high grade tumors. Using this GRN we nominate ANXA1 and HMOX1 as surrogate cell surface markers for activation, thus permitting prospective isolation and functional validation in human GAMs. These cells, termed malignancy associated GAMs (mGAMs) are pro-invasive, pro-angiogenic, pro-proliferative, possess intact antigen presentation but skew T-cells towards a CD4+FOXP3+ phenotype under hypoxia. Ontologically, mGAMs share somatic mitochondrial mutations with peripheral blood monocytes, and their presence correlates with high grade disease irrespective of underlying tumor mutation status. Furthermore, spatio-temporally mGAMs occupy distinct metabolic niches; mGAMs directly induce proliferation and mesenchymal transition of low grade glioma cells and accelerate tumor growth in vivo upon co-culture. Finally mGAMs are preferentially enriched in patients with newly transformed regions in human gliomas, supporting the view that mGAMs play a pivotal role in glioma progression and may represent a plausible therapeutic target in human high-grade glioma.

DOI: https://doi.org/10.1101/2025.02.12.637857
Neurooncol Adv. 2025 Jan-Dec;7(1):7(1): vdaf024

Longitudinal profiling of IDH-mutant astrocytomas reveals acquired RAS-MAPK pathway mutations associated with inferior survival.

Eduardo Rodriguez Almaraz, Geno A Guerra, Nadeem N Al-Adli, Jacob S Young, Abraham Dada, Daniel Quintana, Jennie W Taylor, Nancy Ann Oberheim Bush, Jennifer L Clarke, Nicholas A Butowski, John de Groot, Melike Pekmezci, Arie Perry, Andrew W Bollen, Aaron W Scheffler, David V Glidden, Joanna J Phillips, Joseph F Costello, Edward F Chang, Shawn Hervey-Jumper, Mitchel S Berger, Stephen S Francis, Susan M Chang, David A Solomon.

   Background: Isocitrate dehydrogenase (IDH)-mutant astrocytomas represent the most frequent primary intraparenchymal brain tumor in young adults, which typically arise as low-grade neoplasms that often progress and transform to higher grade despite current therapeutic approaches. However, the genetic alterations underlying high-grade transformation and disease progression of IDH-mutant astrocytomas remain inadequately defined.
Methods: Genomic profiling was performed on 205 IDH-mutant astrocytomas from 172 patients from both initial treatment-naive and recurrent post-treatment tumor specimens. Molecular findings were integrated with clinical outcomes and pathologic features to define the associations of novel genetic alterations in the RAS-MAPK signaling pathway.
Results: Likely oncogenic alterations within the RAS-MAPK mitogenic signaling pathway were identified in 13% of IDH-mutant astrocytomas, which involved the KRAS, NRAS, BRAF, NF1, SPRED1, and LZTR1 genes. These included focal amplifications and known activating mutations in oncogenic components (e.g. KRAS, BRAF), as well as deletions and truncating mutations in negative regulatory components (e.g. NF1, SPRED1). These RAS-MAPK pathway alterations were enriched in recurrent tumors and occurred nearly always in high-grade tumors, often co-occurring with CDKN2A homozygous deletion. Patients whose IDH-mutant astrocytomas harbored these oncogenic RAS-MAPK pathway alterations had inferior survival compared to those with RAS-MAPK wild-type tumors.
Conclusions: These findings highlight novel genetic perturbations in the RAS-MAPK pathway as a likely mechanism contributing to the high-grade transformation and treatment resistance of IDH-mutant astrocytomas that may be a potential therapeutic target for affected patients and used for future risk stratification.

Keywords:  IDH1 mutation; RAS-MAPK signaling pathway; astrocytoma; glioma; molecular neuropathology

DOI:  https://doi.org/10.1093/noajnl/vdaf024
bioRxiv. 2024 Dec 20. pii: 2024.12.20.629544. [Epub ahead of print]

Three-dimensional regulatory hubs support oncogenic programs in glioblastoma.

Sarah L Breves, Dafne Campigli Di Giammartino, James Nicholson, Stefano Cirigliano, Syed Raza Mahmood, Uk Jin Lee, Alexander Martinez-Fundichely, Johannes Jungverdorben, Richa Singhania, Sandy Rajkumar, Raphael Kirou, Lorenz Studer, Ekta Khurana, Alexander Polyzos, Howard A Fine, Effie Apostolou.

Dysregulation of enhancer-promoter communication in the context of the three-dimensional (3D) nucleus is increasingly recognized as a potential driver of oncogenic programs. Here, we profiled the 3D enhancer-promoter networks of primary patient-derived glioblastoma stem cells (GSCs) in comparison with neuronal stem cells (NSCs) to identify potential central nodes and vulnerabilities in the regulatory logic of this devastating cancer. Specifically, we focused on hyperconnected 3D regulatory hubs and demonstrated that hub-interacting genes exhibit high and coordinated expression at the single-cell level and strong association with oncogenic programs that distinguish IDH-wt glioblastoma patients from low-grade glioma. Epigenetic silencing of a recurrent 3D enhancer hub-with an uncharacterized role in glioblastoma-was sufficient to cause concordant downregulation of multiple hub-connected genes along with significant shifts in transcriptional states and reduced clonogenicity. By integrating published datasets from other cancer types, we also identified both universal and cancer type-specific 3D regulatory hubs which enrich for varying oncogenic programs and nominate specific factors associated with worse outcomes. Genetic alterations, such as focal duplications, could explain only a small fraction of the detected hyperconnected hubs and their increased activity. Overall, our study provides computational and experimental support for the potential central role of 3D regulatory hubs in controlling oncogenic programs and properties.
HIGHLIGHTS: - 3D regulatory "hubs" in glioblastoma enrich for highly coregulated genes at a single-cell level and expand oncogenic regulatory networks.- Targeted perturbation of a highly recurrent 3D regulatory hub in GSCs results in altered transcriptional states and cellular properties.- 3D regulatory hubs across cancer types associate with tumor-specific and universal oncogenic programs and worse outcomes.- The majority of hyperconnected hubs do not overlap with structural variants, suggesting epigenetic mechanisms.
eTOC: Here we profile the 3D enhancer connectomes of primary patient-derived human glioblastoma stem cells (GSCs), identify hyperconnected 3D regulatory "hubs", and examine the impact of 3D hub perturbation on the transcriptional program and oncogenic properties.

DOI: https://doi.org/10.1101/2024.12.20.629544
Neuro Oncol. 2025 Mar 03. pii: noaf058. [Epub ahead of print]

Applications of Artificial Intelligence and Advanced Imaging in Pediatric Diffuse Midline Glioma.

Atlas Haddadi Avval, Suneel Banerjee, John Zielke, Benjamin Kann, Sabine Mueller, Andreas M Rauschecker.

  Diffuse Midline Glioma (DMG) is a rare, aggressive, and fatal tumor that largely occurs in the pediatric population. To improve outcomes, it is important to characterize DMGs, which can be performed via MRI assessment. Recently, artificial intelligence (AI) and advanced imaging have demonstrated their potential to improve the evaluation of various brain tumors, gleaning more information from imaging data than is possible without these methods. This narrative review compiles the existing literature on the intersection of MRI-based AI use and DMG tumors. The applications of AI in DMG revolve around classification and diagnosis, segmentation, radiogenomics, and prognosis/survival prediction. Currently published articles have utilized a wide spectrum of AI algorithms, from traditional machine learning and radiomics to neural networks. Challenges include the lack of cohorts of DMG patients with publicly available, multi-institutional, multimodal imaging and genomics datasets as well as the overall rarity of the disease. As an adjunct to AI, advanced MRI techniques, including Diffusion Weighted Imaging (DWI), Perfusion Weighted Imaging (PWI), and Magnetic Resonance Spectroscopy (MRS), as well as Positron Emission Tomography (PET), provide additional insights into DMGs. Establishing AI models in conjunction with advanced imaging modalities has the potential to push clinical practice toward precision medicine.

Keywords:  Artificial Intelligence; Deep Learning; Diffuse Intrinsic Pontine Glioma; Diffuse Midline Glioma; Radiomics

DOI:  https://doi.org/10.1093/neuonc/noaf058
Clin Cancer Res. 2025 Feb 28.

Personalized tumor-specific amplified DNA junctions in peripheral blood of patients with glioblastoma.

Mohamed F Ali, Cecile Riviere-Cazaux, Sarah H Johnson, Rebecca Salvatori, Alan R Penheiter, James B Smadbeck, Stephen J Murphy, Faye R Harris, Lex F McCune, Lucas P Carlstrom, Michael T Barrett, Farhad Kosari, Leila A Jones, Cristiane Ida, Mitesh J Borad, Bernard R Bendok, Alfredo Quiñones-Hinojosa, Alyx B Porter, Maciej M Mrugala, Kurt A Jaeckle, Panos Z Anastasiadis, Sani H Kizilbash, John C Cheville, David M Routman, Terry C Burns, George Vasmatzis.

PURPOSE: Monitoring disease progression in patients with high-grade gliomas (HGGs) is challenging due to treatment-related changes on imaging and the requirement for neurosurgical intervention to obtain diagnostic tissue. DNA junctions in HGGs often amplify oncogenes, making these DNA fragments potentially more abundant in blood than monoallelic mutations. Herein, we piloted a cell-free DNA approach for disease detection in plasma of patients with HGGs by leveraging patient-specific DNA junctions associated with oncogene amplifications.
EXPERIMENTAL DESIGN: Whole genome sequencing of grade 3 or 4 IDH-mutant or wild-type astrocytomas was utilized to identify amplified junctions. Individualized qPCR assays were developed using patient-specific primers designed for the amplified junction. ctDNA levels containing these junctions were measured in patient plasma samples.
RESULTS: Unique amplified junctions were evaluated by individualized semi-quantitative PCR assays in presurgical plasma of 18 patients, 15 with tumor-associated focal amplifications and three without. High-copy number junctions were robustly detected in plasma of 14/15 patients (93.3%) with amplified junctions and none of the controls. Changes in junction abundance correlated with disease trajectory in serial plasma samples from five patients, including increased abundance of amplified junctions preceding radiographic disease progression.
CONCLUSION: In patients with grade 3 or 4 astrocytomas who had tumor-associated amplifications, patient-specific amplified junctions were successfully detected in assayed plasma from most patients. Longitudinal analysis of plasma samples correlated with disease trajectory, including cytoreduction and progression.

DOI: https://doi.org/10.1158/1078-0432.CCR-24-3233
Cell Rep. 2025 Mar 05. pii: S2211-1247(25)00132-9. [Epub ahead of print]44(3): 115361

ARHGAP12 and ARHGAP29 exert distinct regulatory effects on switching between two cell morphological states through GSK-3 activity.

Vinton W T Cheng, Philippa Vaughn-Beaucaire, Gary C Shaw, Malte Kriegs, Alastair Droop, George Psakis, Michel Mittelbronn, Matt Humphries, Filomena Esteves, Josie Hayes, Julia V Cockle, Sabine Knipp, Arndt Rohwedder, Azzam Ismail, Ola Rominiyi, Spencer J Collis, Georgia Mavria, James Samarasekara, John E Ladbury, Sophie Ketchen, Ruth Morton, Sarah Fagan, Daniel Tams, Katie Myers, Connor McGarrity-Cottrell, Mark Dunning, Marjorie Boissinot, George Michalopoulos, Sally Prior, Yun Wah Lam, Ewan E Morrison, Susan C Short, Sean E Lawler, Anke Brüning-Richardson.

  Cancer cells undergo morphological changes and phenotype switching to promote invasion into healthy tissues. Manipulating the transitional morphological states in cancer cells to prevent tumor dissemination may enhance survival and improve treatment response. We describe two members of the RhoGTPase activating protein (ARHGAP) family, ARHGAP12 and ARHGAP29, as regulators of transitional morphological states in glioma via Src kinase signaling events, leading to morphological changes that correspond to phenotype switching. Moreover, we establish a link between glycogen synthase kinase 3 (GSK-3) inhibition and β-catenin translocation in altering transcription of ARHGAP12 and ARHGAP29. Silencing ARHGAP12 causes loss of N-cadherin and adoption of mesenchymal morphology, a characteristic feature of aggressive cellular behavior. In patients with glioblastoma (GBM), we identify a link between ARHGAP12 and ARHGAP29 co-expression and recurrence after treatment. Consequently, we propose that further investigation of how ARHGAPs regulate transitional morphological events to drive cancer dissemination is warranted.

Keywords:  BIO-indirubin; CP: Cancer; RhoGTPase activating protein; Src kinase signaling; cell morphology; glioma; glycogen synthase kinase 3; tumor recurrence

DOI:  https://doi.org/10.1016/j.celrep.2025.115361
Cancer Res. 2025 Mar 07.

Targeting the SP/KLF Transcriptional Regulatory Network Synergizes with HDAC Inhibition to Impede Progression of H3K27M Diffuse Intrinsic Pontine Glioma.

Yu Kong, Fan Wang, Renwei Jing, Qian Zhao, Xuejiao Lv, Yingying Zhao, Ye Yuan, Xianyou Xia, Yu Sun, Yujie Tong, Han Yan, Qian Li, Ting Li, Lei Cao, Deng Liu, Dawei Huo, Shao-Kai Sun, Francisco Morís, Yujie Tang, Xudong Wu.

Diffuse intrinsic pontine gliomas (DIPGs) are lethal pediatric brain tumors that frequently harbor H3K27M mutations and lack effective treatments. Here, our epigenomic analyses uncovered an enrichment of SP/KLF transcription factors in open chromatin regions specifically in H3K27M-mutated DIPG cells compared to normal pontine neural progenitor cells. SP1 depletion or inhibition of SP/KLF DNA binding with EC-8042, an optimized mithramycin analog, significantly suppressed the proliferation and invasiveness of H3K27M-DIPG cells. A screen of epigenetic drugs showed that histone deacetylase inhibitors (HDACi) synergized with EC-8042 to suppress H3K27M-DIPG cell growth. Unexpectedly, HDACi activated transcriptional programs that enhanced tumor adaptability and invasiveness, an effect counteracted by EC-8042. Mechanistically, HDACi treatment enhanced chromatin accessibility to SP/KLF factors, while EC-8042 disrupted both the primary SP/KLF transcription regulatory network and the HDACi-induced secondary network. Consequently, the combination treatment significantly impeded tumor progression in orthotopic xenograft models. Transcriptomic profiling indicated that this combinatorial strategy induced transcriptional changes associated with improved prognosis in DIPG patients. Thus, this study identifies a therapeutic approach for H3K27M-mutated DIPGs and sheds light on the limitations of HDACi in treating solid tumors.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-2227