bims-malgli 2025-07-27 papers

Issue of 2025–07–27
five papers selected by
Oltea Sampetrean, Keio University

Oncogene. 2025 Jul 18.

Unveiling the role of TAM-derived extracellular vesicles in glioma progression through Treg polarization and immune suppression.

Shoudan Zhang, Lin Zhang, Ning Guan, Xu Feng, Miaomiao Lu, Yanyun Wang.

In the context of gliomas, tumor-associated macrophages (TAMs) and regulatory T cells (Tregs) play crucial roles in shaping the tumor microenvironment (TME). This study focused on elucidating the mechanism by which TAM-derived extracellular vesicles (EVs) influence Treg differentiation and contribute to glioma progression. Through comprehensive single-cell RNA sequencing (scRNA-seq) analysis, the glioma TME was characterized by an abundance of TAMs exhibiting M2 polarization and increased Treg differentiation. Notably, TAM EVs were identified as potent inducers of Treg differentiation, with the downregulation of Bactericidal/Permeability-Increasing protein (BPI) being associated with this process. In vivo experiments utilizing a mouse model of glioma further demonstrated that TAM-derived EVs promoted glioma growth by enhancing Treg-mediated immunosuppression while dampening pro-inflammatory responses. This study highlights the critical role of TAM-derived EVs in modulating Treg differentiation and supporting glioma progression, suggesting that interventions targeting TAM EVs or regulating BPI expression could offer novel therapeutic avenues for combating immune suppression and inhibiting glioma development.

DOI: https://doi.org/10.1038/s41388-025-03497-8

Nat Commun. 2025 Jul 19. 16(1): 6662

The invasion phenotypes of glioblastoma depend on plastic and reprogrammable cell states.

Milena Doroszko, Rebecka Stockgard, Irem Uppman, Josephine Heinold, Faidra Voukelatou, Hitesh Bhagavanbhai Mangukiya, Thomas O Millner, Madeleine Skeppås, Mar Ballester Bravo, Ramy Elgendy, Maria Berglund, Ludmila Elfineh, Cecilia Krona, Soumi Kundu, Katarzyna Koltowska, Silvia Marino, Ida Larsson, Sven Nelander.

Glioblastoma (GBM) is the most common primary brain cancer. It causes death mainly by local invasion via several routes, including infiltration of white matter tracts and penetration of perivascular spaces. However, the pathways that mediate these invasion routes are only partly known. Here, we conduct an integrative study to identify cell states and central drivers of route-specific invasion in GBM. Combining single-cell profiling and spatial protein detection in patient-derived xenograft models and clinical tumor samples, we demonstrate a close association between the differentiation state of GBM cells and their choice of invasion route. Computational modeling identifies ANXA1 as a driver of perivascular involvement in GBM cells with mesenchymal differentiation and the transcription factors RFX4 and HOPX as orchestrators of growth and differentiation in diffusely invading GBM cells. Ablation of these targets in tumor cells alters their invasion route, redistributes the cell states, and extends survival in xenografted mice. Our results define a close association between GBM cell differentiation states and invasion routes, identify functional biomarkers of route-specific invasion, and point toward targeted modulation of specific invasive cell states as a therapeutic strategy in GBM.

DOI: https://doi.org/10.1038/s41467-025-61999-1

bioRxiv. 2025 Jul 19. pii: 2025.07.18.665585. [Epub ahead of print]

SUZ12-Nucleic Acid Interactions Constrain PRC2 Activity to Maintain Targeted Gene Silencing Essential to Diffuse Midline Glioma.

Tyler J Reich, Paul A Clark, Audrey Baguette, Joanna K Lempiainen, Caterina Russo, Andrew Q Rashoff, Truman J Do, Benjamin A Garcia, Claudia L Kleinman, Nada Jabado, Zachary S Morris, Peter W Lewis.

Polycomb Repressive Complex 2 (PRC2) mediates transcriptional silencing through trimethylation of histone H3 at lysine 27 (H3K27me3), an epigenetic modification critical for development and frequently altered in cancer. Pediatric diffuse midline gliomas (DMGs) bearing the histone H3 K27M mutation exhibit global loss of H3K27me3 due to dominant inhibition of PRC2 by the mutant histone. Despite widespread hypomethylation, focal retention of H3K27me3 persists, and tumor cells maintain dependency on residual PRC2 activity for proliferation. The molecular basis underlying this residual enzymatic function and its regulation remain poorly defined. To address this mechanism, we investigated the role of SUZ12, the architectural core of PRC2 that facilitates interactions with accessory subunits. We identified the SUZ12 N-terminal region as a regulatory domain that constrains PRC2 catalytic activity through transient interactions with nucleic acids, thereby limiting non-specific chromatin engagement. Expression of a truncated SUZ12 variant retaining the catalytic VEFS domain, but lacking the nucleic acid-binding regulatory elements, led to widespread H3K27 hypermethylation, displacement of canonical PRC1 complexes, disruption of chromatin architecture, and impaired H3 K27M glioma cell growth in vitro and in vivo . Biochemical analyses revealed a SUZ12 N-terminal domain that modulates PRC2 activity by promoting non-productive binding to nucleic acids, thus establishing a kinetic equilibrium essential for precise chromatin targeting. These findings redefine Polycomb specificity as a dynamic equilibrium between productive nucleosomal engagement and non-productive nucleic acid interactions, providing critical insights into PRC2 regulation and highlighting potential therapeutic vulnerabilities in PRC2-dependent cancers.

DOI: https://doi.org/10.1101/2025.07.18.665585

Neuro Oncol. 2025 Jul 19. pii: noaf169. [Epub ahead of print]

BRD2 Bromodomain-Mediated Regulation of Cell State Plasticity Modulates Therapy Response in Glioblastoma.

Raghavendra Vadla, Brett Taylor, Yohei Miyake, Benjamin Lin, Daisuke Kawauchi, Shunichiro Miki, Nidhi Nathwani, Brandon M Jones, Yashpreet Kaur, Abhinaba Banerjee, Philip Pham, Jonathan Tsang, Albert Baldwin, David A Nathanson, Donald P Pizzo, C Ryan Miller, Frank B Furnari.

BACKGROUND: Glioblastoma (GBM) displays remarkable cell state plasticity, a major contributor to therapeutic resistance and tumor progression. While epigenetic mechanisms play a central role in driving this plasticity, the key regulators remain poorly understood, and developing effective therapeutic strategies targeting them has been challenging.
METHODS: We investigated the role of BRD2, a key regulator of NF-κB mediated mesenchymal (MES) transition, using GBM patient-derived xenograft (PDX) cell lines, CRISPR-mediated knock-in/knockout approaches, RNA-seq, and in vitro and in vivo modeling. BET inhibitors were employed to target MES gene expression and sensitize GBM to radiation therapy.
RESULTS: We found that PTEN loss induces RelA chromatin localization and acetylation-mediated recruitment of BRD2 to the MES gene promoters. BRD2 binding is essential for maintaining MES gene expression and phenotype. Genetic ablation or loss-of-function mutation of BRD2 bromodomains reverses MES transition, enhances radiation sensitivity, and improves survival in orthotopic xenograft models. Additionally, treatment with a brain-penetrant BD2-selective inhibitor suppresses the MES phenotype and increases radiation sensitivity of GBM stem cells in vitro.
CONCLUSION: Our study identifies BRD2 as a key mediator of MES transition in GBM, with its bromodomains playing a crucial role in driving cell state plasticity. Targeting BRD2 with BD2-selective inhibitors offers a promising therapeutic strategy to overcome radiation resistance and improve outcomes for GBM patients.

Keywords: BET inhibitors; BRD2; Glioblastoma; Mesenchymal; NF-κB signaling

DOI: https://doi.org/10.1093/neuonc/noaf169

Sci Adv. 2025 Jul 25. 11(30): eadw8330

Construction of a whole-brain panorama for glioma vasculature reveals tumor heterogeneity and blood-brain barrier disruption.

Chenxi Huang, Xiaohong Xin, Xiaoxu Hao, Shilin Zhou, Zongneng Xie, Lijuan He, Xiaoliang Li, Yu Zhang, Hongyu Sun, Jiwen Zhang, Xiaochuan Zhang, Xianzhen Yin.

Vasculature-induced tumor tissue heterogeneity impedes predicable drug distribution and presents notable challenges for optimizing nanoparticle (NP)-based drug delivery. However, mesoscopic-scale tumor heterogeneity across entire brain remains poorly characterized. To address this, we integrated micro-optical sectioning tomography (MOST) with high-precision three-dimensional (3D) reconstruction analysis to map pathological features of orthotopic glioma at submicron resolution across whole mice brain. Our findings uncovered significant heterogeneity in glioma invasiveness, vasculature, and compensatory angiogenesis while precisely delineating NP distribution throughout the tumor. Notably, early-stage glioma co-opted and migrated 680-micrometer upstream along the main cerebral artery within 4 days after glioma implantation. Blood-brain barrier permeability gradually increased during glioma progression, enabling NP penetrated via large-diameter vessels instead being restricted to capillaries. This work establishes a multiscale, high-resolution, 3D atlas of glioma heterogeneity and NP distribution, and bridges mesoscopic structural complexity to functional drug delivery barriers, advancing strategies to enhance oncotherapy precision in heterogeneous brain tumors.

DOI: https://doi.org/10.1126/sciadv.adw8330