bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2025–05–11
eleven papers selected by
Oltea Sampetrean, Keio University
  1. KAT5 regulates neurodevelopmental states associated with G0-like populations in glioblastoma.
  2. Nuclear NAD+ synthase nicotinamide mononucleotide adenylyltransferase 1 contributes to nuclear atypia and promotes glioma growth.
  3. Somatic mutations in HLA class genes and antigen presenting molecules in malignant glioma.
  4. Genomic landscape of diffuse glioma revealed by whole genome sequencing.
  5. Complex neural-immune interactions shape glioma immunotherapy.
  6. Consortium trial demonstrates efficacy of Selumetinib in pediatric low-grade glioma.
  7. Deciphering the dialogue between brain tumors, neurons, and astrocytes.
  8. Functional mitochondrial respiration is essential for glioblastoma tumour growth.
  9. The multilayered transcriptional architecture of glioblastoma ecosystems.
  10. Deciphering the longitudinal trajectories of glioblastoma ecosystems by integrative single-cell genomics.
  11. Multiomic profiling of glioblastoma metabolic lesions reveals complex intratumoral genomic evolution and dipeptidase-1-driven vascular proliferation.
  1. Nat Commun. 2025 May 09. 16(1): 4327
    KAT5 regulates neurodevelopmental states associated with G0-like populations in glioblastoma.
    Anca B Mihalas, Sonali Arora, Samantha A O'Connor, Heather M Feldman, Christine E Cucinotta, Kelly Mitchell, John Bassett, Dayoung Kim, Kang Jin, Pia Hoellerbauer, Jennifer Delegard, Melissa Ling, Wesley Jenkins, Megan Kufeld, Philip Corrin, Lucas Carter, Toshio Tsukiyama, Bruce Aronow, Christopher L Plaisier, Anoop P Patel, Patrick J Paddison.
      Quiescence cancer stem-like cells may play key roles in promoting tumor cell heterogeneity and recurrence for many tumors, including glioblastoma (GBM). Here we show that the protein acetyltransferase KAT5 is a key regulator of transcriptional, epigenetic, and proliferative heterogeneity impacting transitions into G0-like states in GBM. KAT5 activity suppresses the emergence of quiescent subpopulations with neurodevelopmental progenitor characteristics, while promoting GBM stem-like cell (GSC) self-renewal through coordinately regulating E2F- and MYC- transcriptional networks with protein translation. KAT5 inactivation significantly decreases tumor progression and invasive behavior while increasing survival after standard of care. Further, increasing MYC expression in human neural stem cells stimulates KAT5 activity and protein translation, as well as confers sensitivity to homoharringtonine, to similar levels to those found in GSCs and high-grade gliomas. These results suggest that the dynamic behavior of KAT5 plays key roles in G0 ingress/egress, adoption of quasi-neurodevelopmental states, and aggressive tumor growth in gliomas.
    DOI:  https://doi.org/10.1038/s41467-025-59503-w
  2. Neurooncol Adv. 2025 Jan-Dec;7(1):7(1): vdaf029
    Nuclear NAD+ synthase nicotinamide mononucleotide adenylyltransferase 1 contributes to nuclear atypia and promotes glioma growth.
    Jiaqi Liu, Yi Zhu, Tijana Canic, Zoraida Diaz-Perez, Sakir Humayun Gultekin, R Grace Zhai.
       Background: Glioma is a malignant primary brain tumor with a poor prognosis and short survival. NAD+ is critical for cancer growth; however, clinical trials targeting NAD+ biosynthesis had limited success, indicating the need for mechanistic characterization. Nuclear atypia, aberrations in the size and shape of the nucleus, is widely observed in cancer and is often considered a distinctive feature in diagnosis; however, the molecular underpinnings are unclear.
    Methods: We carried out high-resolution immunohistochemical analyses on glioma tissue samples from 19 patients to analyze the expression of NAD+ synthase nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1), and its correlation with nuclear atypia in gliomas. Utilizing a Drosophila model of glial neoplasia, we investigated the genetic role of nuclear NMNAT in glioma growth in vivo, elucidating the cellular mechanisms of NMNAT1 in promoting nuclear atypia and glioma growth.
    Results: In low-grade glioma and glioblastoma, a higher transcription level of NMNAT1 is correlated with poorer disease-free survival. Samples of high-grade gliomas contained a higher percentage of glial cells enriched with NMNAT1 protein. We identified a specific correlation between nuclear NMNAT1 protein level with nuclear atypia. Mechanistic studies in human glioma cell lines and in vivo Drosophila model suggest that NMNAT1 disrupts the integrity of the nuclear lamina by altering the distribution of lamin A/C and promotes glioma growth.
    Conclusions: Our study uncovers a novel functional connection between the NAD+ metabolic pathway and glioma growth, reveals the contribution of the NAD+ biosynthetic enzyme NMNAT1 to nuclear atypia, and underscores the role of nuclear NMNAT1 in exacerbating glioma pathology.
    Keywords:  Drosophila; EGFR; NAD+; glioblastoma; lamin A/C
    DOI:  https://doi.org/10.1093/noajnl/vdaf029
  3. Cancer Immunol Res. 2025 May 05.
    Somatic mutations in HLA class genes and antigen presenting molecules in malignant glioma.
    Sara C Schulte, Wolfgang Peter, Georg Rosenberger, Moritz Schäfer, Cecile L Maire, Alessandra Rünger, Alice Ryba, Kristoffer Riecken, Krystian D Fita, Jakob Matschke, Nuray Akyüz, Judith Dierlamm, Gunnar W Klau, Franz L Ricklefs, Jens Gempt, Manfred Westphal, Katrin Lamszus, Alexander Dilthey, Malte Mohme.
      Immune evasion is a hallmark of gliomas, yet the genetic mechanisms by which tumors escape immune surveillance remain incompletely understood. In this study, we systematically examined the presence of somatic mutations in human leukocyte antigen (HLA) genes and genes encoding proteins involved in antigen-presentation across isocitrate dehydrogenase wild-type (IDHwt) and mutant (IDHmut) gliomas using targeted next-generation sequencing (NGS). To address the challenges associated with detecting somatic mutations in these highly polymorphic and complex regions of the genome, we applied a combination of short-read and long-read sequencing techniques, extended the genetic region of interest (exons and introns), and applied a tailored bioinformatics analysis pipeline, which enabled an accurate evaluation of comprehensive sequencing data. Our analysis identified mutations in HLA class II and non-classical HLA genes as well as genes associated with antigen presentation, such as TAP1/2 and B2M. Three-dimensional modeling of individual mutations simulated the potential impact of somatic mutations in TAP1 and B2M on the encoded protein configuration. The presence of somatic mutations supports the role of antigen-presenting genes in the pathophysiology and potential immune escape of gliomas. Our data demonstrated an increased frequency of such mutations in recurrent glioblastoma (GBM), potentially resulting from a positive selection or mutagenic enrichment of tumor cells during tumor progression. Taken together, this research generates new insights and hypotheses for the functional analysis and optimization of immunotherapy strategies for gliomas, which may guide personalized treatment paradigms.
    DOI:  https://doi.org/10.1158/2326-6066.CIR-24-0419
  4. Nat Commun. 2025 May 07. 16(1): 4233
    Genomic landscape of diffuse glioma revealed by whole genome sequencing.
    Ben Kinnersley, Josephine Jung, Alex J Cornish, Daniel Chubb, Ross Laxton, Anna Frangou, Andreas J Gruber, Amit Sud, Giulio Caravagna, Andrea Sottoriva, David C Wedge, Thomas Booth, Safa Al-Sarraj, Samuel E D Lawrence, Erminia Albanese, Giulio Anichini, David Baxter, Alexandros Boukas, Yasir A Chowdhury, Pietro D'Urso, Robert Corns, Andrew Dapaah, Ellie Edlmann, Fay Greenway, Paul Grundy, Ciaran S Hill, Michael D Jenkinson, Sandhya Trichinopoly Krishna, Stuart Smith, Susruta Manivannan, Andrew J Martin, Samir Matloob, Soumya Mukherjee, Kevin O'Neill, Puneet Plaha, Jonathan Pollock, Stephen Price, Ola Rominiyi, Bobby Sachdev, Fozia Saeed, Saurabh Sinha, Lewis Thorne, Ismail Ughratdar, Peter Whitfield, Amir Saam Youshani, Helen Bulbeck, Prabhu Arumugam, Richard Houlston, Keyoumars Ashkan.
      Diffuse gliomas are the commonest malignant primary brain tumour in adults. Herein, we present analysis of the genomic landscape of adult glioma, by whole genome sequencing of 403 tumours (256 glioblastoma, 89 astrocytoma, 58 oligodendroglioma; 338 primary, 65 recurrence). We identify an extended catalogue of recurrent coding and non-coding genetic mutations that represents a source for future studies and provides a high-resolution map of structural variants, copy number changes and global genome features including telomere length, mutational signatures and extrachromosomal DNA. Finally, we relate these to clinical outcome. As well as identifying drug targets for treatment of glioma our findings offer the prospect of improving treatment allocation with established targeted therapies.
    DOI:  https://doi.org/10.1038/s41467-025-59156-9
  5. Immunity. 2025 May 02. pii: S1074-7613(25)00180-3. [Epub ahead of print]
    Complex neural-immune interactions shape glioma immunotherapy.
    Kun-Wei Song, Michael Lim, Michelle Monje.
      Rich neural-immune interactions in the central nervous system (CNS) shape its function and create a unique immunological microenvironment for immunotherapy in CNS malignancies. Far from the now-debunked concept of CNS "immune privilege," it is now understood that unique immunological niches and constant immune surveillance of the brain contribute in multifaceted ways to brain health and robustly influence immunotherapy approaches for CNS cancers. Challenges include immune-suppressive and neurotoxicity-promoting crosstalk between brain, immune, and tumor cells. Developing effective immunotherapies for cancers of the nervous system will require a deeper understanding of these neural-immune-malignant cell interactions. Here, we review progress and challenges in immunotherapy for gliomas of the brain and spinal cord in light of these unique neural-immune interactions and highlight future work needed to optimize promising immunotherapies for gliomas.
    Keywords:  CAR T cells; DIPG/DMG; brain borders; central nervous system; glioblastoma; immunotherapy
    DOI:  https://doi.org/10.1016/j.immuni.2025.04.017
  6. Neuro Oncol. 2025 May 08. pii: noaf119. [Epub ahead of print]
    Consortium trial demonstrates efficacy of Selumetinib in pediatric low-grade glioma.
    Anirban Das.
      
    Keywords:  MEK inhibition; low grade glioma; targeted therapy
    DOI:  https://doi.org/10.1093/neuonc/noaf119
  7. Am J Pathol. 2025 May 07. pii: S0002-9440(25)00153-1. [Epub ahead of print]
    Deciphering the dialogue between brain tumors, neurons, and astrocytes.
    Leevi H Westerlund, Camilla K Bergström, Pirjo M Laakkonen, Vadim Le Joncour.
      Glioblastoma (GB) and brain metastases (BM) from peripheral tumors account for most cases of tumors in the central nervous system (CNS) while also being the deadliest. From a structural point of view, malignant brain tumors are classically characterized by hypercellularity of glioma and vascular endothelial cells. Given these atypical histological features, GB and BM have long been considered as "foreign" entities with few to no connections to the brain parenchyma. The identification of intricate connections established between GB cells and the brain parenchyma paired with the ability of peripheral metastatic cells to form functional synapses with neurons, challenged the concept of brain tumors disconnected from the CNS. In patients, tumor cell integration to the CNS alters brain functionality and accelerates cancer progression. Next generation precision medicine should therefore attempt to disconnect brain cancer cells from the brain. This review encompasses recent discoveries on the mechanisms underlying these relationships and discusses the impact of these connections on tumor progression, and summarizes the therapeutic opportunities of interrupting the dialogue between healthy and neoplastic brains.
    Keywords:  brain metastasis; cancer neuroscience; cellular plasticity; glioblastoma; paracrine signaling; tumor microenvironment; tumor synapses
    DOI:  https://doi.org/10.1016/j.ajpath.2025.04.013
  8. Oncogene. 2025 May 05.
    Functional mitochondrial respiration is essential for glioblastoma tumour growth.
    Petra Brisudova, Dana Stojanovic, Jaromir Novak, Zuzana Nahacka, Gabriela Lopes Oliveira, Ondrej Vanatko, Sarka Dvorakova, Berwini Endaya, Jaroslav Truksa, Monika Kubiskova, Alice Foltynova, Daniel Jirak, Natalia Jirat-Ziolkowska, Lukas Kucera, Karel Chalupsky, Krystof Klima, Jan Prochazka, Radislav Sedlacek, Francesco Mengarelli, Patrick Orlando, Luca Tiano, Paulo Oliveira, Carole Grasso, Michael V Berridge, Renata Zobalova, Miroslava Anderova, Jiri Neuzil.
      Horizontal transfer of mitochondria from the tumour microenvironment to cancer cells to support proliferation and enhance tumour progression has been shown for various types of cancer in recent years. Glioblastoma, the most aggressive adult brain tumour, has proven to be no exception when it comes to dynamic intercellular mitochondrial movement, as shown in this study using an orthotopic tumour model of respiration-deficient glioblastoma cells. Although confirmed mitochondrial transfer was shown to facilitate tumour progression in glioblastoma, we decided to investigate whether the related electron transport chain recovery is necessary for tumour formation in the brain. Based on experiments using time-resolved analysis of tumour formation by glioblastoma cells depleted of their mitochondrial DNA, we conclude that functional mitochondrial respiration is essential for glioblastoma growth in vivo, because it is needed to support coenzyme Q redox cycling for de novo pyrimidine biosynthesis controlled by respiration-linked dihydroorotate dehydrogenase enzyme activity. We also demonstrate here that astrocytes are key mitochondrial donors in this model.
    DOI:  https://doi.org/10.1038/s41388-025-03429-6
  9. Nat Genet. 2025 May 09.
    The multilayered transcriptional architecture of glioblastoma ecosystems.
    Masashi Nomura, Avishay Spitzer, Kevin C Johnson, Luciano Garofano, Djamel Nehar-Belaid, Noam Galili Darnell, Alissa C Greenwald, Lillian Bussema, Young Taek Oh, Frederick S Varn, Fulvio D'Angelo, Simon Gritsch, Kevin J Anderson, Simona Migliozzi, L Nicolas Gonzalez Castro, Tamrin ChowdhFury, Nicolas Robine, Catherine Reeves, Jong Bae Park, Anuja Lipsa, Frank Hertel, Anna Golebiewska, Simone P Niclou, Labeeba Nusrat, Sorcha Kellet, Sunit Das, Hyo Eun Moon, Sun Ha Paek, Franck Bielle, Alice Laurenge, Anna Luisa Di Stefano, Bertrand Mathon, Alberto Picca, Marc Sanson, Shota Tanaka, Nobuhito Saito, David M Ashley, Stephen T Keir, Keith L Ligon, Jason T Huse, W K Alfred Yung, Anna Lasorella, Roel G W Verhaak, Antonio Iavarone, Mario L Suvà, Itay Tirosh.
      In isocitrate dehydrogenase wildtype glioblastoma (GBM), cellular heterogeneity across and within tumors may drive therapeutic resistance. Here we analyzed 121 primary and recurrent GBM samples from 59 patients using single-nucleus RNA sequencing and bulk tumor DNA sequencing to characterize GBM transcriptional heterogeneity. First, GBMs can be classified by their broad cellular composition, encompassing malignant and nonmalignant cell types. Second, in each cell type we describe the diversity of cellular states and their pathway activation, particularly an expanded set of malignant cell states, including glial progenitor cell-like, neuronal-like and cilia-like. Third, the remaining variation between GBMs highlights three baseline gene expression programs. These three layers of heterogeneity are interrelated and partially associated with specific genetic aberrations, thereby defining three stereotypic GBM ecosystems. This work provides an unparalleled view of the multilayered transcriptional architecture of GBM. How this architecture evolves during disease progression is addressed in the companion manuscript by Spitzer et al.
    DOI:  https://doi.org/10.1038/s41588-025-02167-5
  10. Nat Genet. 2025 May 09.
    Deciphering the longitudinal trajectories of glioblastoma ecosystems by integrative single-cell genomics.
    Avishay Spitzer, Kevin C Johnson, Masashi Nomura, Luciano Garofano, Djamel Nehar-Belaid, Noam Galili Darnell, Alissa C Greenwald, Lillian Bussema, Young Taek Oh, Frederick S Varn, Fulvio D'Angelo, Simon Gritsch, Kevin J Anderson, Simona Migliozzi, L Nicolas Gonzalez Castro, Tamrin Chowdhury, Nicolas Robine, Catherine Reeves, Jong Bae Park, Anuja Lipsa, Frank Hertel, Anna Golebiewska, Simone P Niclou, Labeeba Nusrat, Sorcha Kellet, Sunit Das, Hyo-Eun Moon, Sun Ha Paek, Franck Bielle, Alice Laurenge, Anna Luisa Di Stefano, Bertrand Mathon, Alberto Picca, Marc Sanson, Shota Tanaka, Nobuhito Saito, David M Ashley, Stephen T Keir, Keith L Ligon, Jason T Huse, W K Alfred Yung, Anna Lasorella, Antonio Iavarone, Roel G W Verhaak, Itay Tirosh, Mario L Suvà.
      The evolution of isocitrate dehydrogenase (IDH)-wildtype glioblastoma (GBM) after standard-of-care therapy remains poorly understood. Here we analyzed matched primary and recurrent GBMs from 59 patients using single-nucleus RNA sequencing and bulk DNA sequencing, assessing the longitudinal evolution of the GBM ecosystem across layers of cellular and molecular heterogeneity. The most consistent change was a lower malignant cell fraction at recurrence and a reciprocal increase in glial and neuronal cell types in the tumor microenvironment (TME). The predominant malignant cell state differed between most matched pairs, but no states were exclusive or highly enriched in either time point, nor was there a consistent longitudinal trajectory across the cohort. Nevertheless, specific trajectories were enriched in subsets of patients. Changes in malignant state abundances mirrored changes in TME composition and baseline profiles, reflecting the co-evolution of the GBM ecosystem. Our study provides a blueprint of GBM's diverse longitudinal trajectories and highlights the treatment and TME modifiers that shape them.
    DOI:  https://doi.org/10.1038/s41588-025-02168-4
  11. Neuro Oncol. 2025 May 04. pii: noaf071. [Epub ahead of print]
    Multiomic profiling of glioblastoma metabolic lesions reveals complex intratumoral genomic evolution and dipeptidase-1-driven vascular proliferation.
    Atul Anand, Jeanette Krogh Petersen, Lars van Brakel Andersen, Mark Burton, Clara Rosa Levina Oudenaarden, Martin Jakob Larsen, Philip Ahle Erichsen, Christian Bonde Pedersen, Frantz Rom Poulsen, Peter Grupe, Torben A Kruse, Mads Thomassen, Bjarne Winther Kristensen.
       BACKGROUND: Glioblastoma undergoes a complex and dynamic evolution involving genetic and epigenetic changes. Understanding the mechanisms underlying this evolution is vital for the development of efficient therapeutic strategies. Although treatment resistance is associated with intratumoral heterogeneity in glioblastoma, it remains uncertain whether hypometabolic and hypermetabolic lesions observed through clinical positron emission tomography (PET) imaging are influenced by spatial intratumoral genomic evolution.
    METHODS: In this study, we precisely isolated autologous hypometabolic and hypermetabolic lesions from glioblastoma using advanced neurosurgical and brain tumor imaging technologies, followed by comprehensive whole-genome, exome, transcriptome, and imaging analyses.
    RESULTS: Our findings unveil that hypermetabolic lesions, originating from hypometabolic lesions, exhibit strategic focal amplifications and deletions, and heightened APOBEC3 activity. Furthermore, we identify dipeptidase 1 as a novel vascular endothelial tip marker for hypermetabolic lesions in glioblastoma, facilitating angiogenesis and tumor metabolism by regulating transporter activities.
    CONCLUSIONS: Hypermetabolic lesions are associated with a higher frequency of genomic abnormalities and dipeptidase 1 emerges as a novel diagnostic and prognostic vascular marker for hypermetabolic lesions. This study underscores a spatial genomic evolution with diagnostic implications and elucidates challenges and opportunities crucial for the development of novel therapeutic strategies.
    Keywords:  Hypermetabolic; dipeptidase 1; mutational burden; tumor evolution; vascular tip
    DOI:  https://doi.org/10.1093/neuonc/noaf071
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