bims-malgli 2025-12-28 papers

bims-malgli

Biomed News

on Biology of malignant gliomas

Issue of 2025–12–28
eleven papers selected by
Oltea Sampetrean, Keio University

Serotonergic neuron-glioma interactions drive high-grade glioma pathophysiology.
Mutation patterns drive mismatch repair-deficient glioma evolution.
Cellular heterogeneity and therapeutic response profiling of human IDH + glioma stem cell cultures.
A biohybrid chiral hydrogel enhances preclinical postoperative glioblastoma therapy by multi-pronged inhibition of tumour stemness.
Concurrent and adjuvant temozolomide for 1p/19q non-co-deleted anaplastic glioma (CATNON; EORTC study 26053-22054): final and exploratory analyses of a randomised, open-label, phase 3 trial.
C/EBPβ-induced alternative splicing of RCAN1 generates a potent TCR-T target in mesenchymal glioblastoma.
Mismatch repair deficiency drives malignant progression and alters the tumor immune microenvironment in glioblastoma models.
The dual-site agonist for human M2 muscarinic receptors Iper-8-naphtalimide induces mitochondrial dysfunction in Saccharomyces cerevisiae.
Patterns of hypermutation shape tumorigenesis and immunotherapy response in mismatch-repair-deficient glioma.
Molecular profiling of glioblastoma-derived extracellular vesicles identifies small nucleolar RNAs as candidate liquid biomarkers for radiation-induced senescence.
Navitoclax acts synergistically with irradiation to induce apoptosis in preclinical models of H3K27M-altered diffuse midline glioma.

bioRxiv. 2025 Dec 12. pii: 2025.12.10.693579. [Epub ahead of print]

Serotonergic neuron-glioma interactions drive high-grade glioma pathophysiology.

Richard Drexler, Belgin Yalçın, Rebecca Mancusi, Abigail Rogers, Kiarash Shamardani, Pamelyn J Woo, Alexandre Ravel, Samuel Wu, Yahaya A Yabo, Lisa Steger, Carlos Alberto Oliveira de Biagi-Junior, Costanza Lo Cascio, Robert Malenka, Boris D Heifets, Mariella G Filbin, Dieter Henrik Heiland, Karl Deisseroth, Michelle Monje.

High-grade gliomas are lethal brain cancers that are powerfully regulated by glutamatergic neurons through activity-dependent paracrine factors and functional neuron-to-glioma synapses. Here, we report that serotonergic neurons promote the proliferation of high-grade gliomas throughout the brain. Serotonergic neuronal activity drives circuit-specific increases in high-grade glioma proliferation, calcium transients, and reduced survival. This growth-promoting effect is chiefly mediated by activation of the serotonin (5-hydroxytryptamine; 5HT) receptor 5HT 2A on glioma cells. Knock out or pharmacological blockade of 5HT 2A receptors in glioma abrogated the glioma growth-promoting effects of serotonergic neuronal activity, while serotonergic psychedelic drugs robustly promote malignant cell proliferation. Gliomas alter serotonergic neuronal activity patterns, resulting in elevated serotonin release into the tumor microenvironment. Together, these findings uncover pathogenic, feed-forward interactions between serotonergic neurons and glioma cells.

DOI: https://doi.org/10.64898/2025.12.10.693579
Nat Genet. 2025 Dec 22.

Mutation patterns drive mismatch repair-deficient glioma evolution.

DOI: https://doi.org/10.1038/s41588-025-02424-7
Sci Rep. 2025 Dec 21.

Cellular heterogeneity and therapeutic response profiling of human IDH + glioma stem cell cultures.

Nyasha Chambwe, Scott R Kennedy, Brendan F Kohrn, Pavlo Lazarchuk, Mario Leutert, Guangrong Qin, Bahar Tercan, Monica Sanchez-Contreras, Weiliang Tang, Jerome J Graber, Patrick J Paddison, Judit Villén, Ilya Shmulevich, Raymond J Monnat.

  Glioblastoma stem cell (GSC) cultures are initiated from glioblastoma (GBM) surgical resection tissue. When grown appropriately they can capture and propagate key GBM molecular and cellular features. We have characterized cellular, genomic and proteomic features of four isocitrate dehydrogenase (IDH)-expressing (IDH +) GSC cultures as cellular models for ~ 90% of adult GBMs. We demonstrate that GSC cultures can be continuously propagated in defined, serum-free media and 5% oxygen without specialized growth substrates; have culture-specific genomic and mtDNA variants together with gene/protein expression profiles; and display reproducible dose-survival curves for the GBM standard-of-care therapies ionizing radiation (IR) and temozolomide (TMZ). In order to better define GSC culture cellular heterogeneity and dynamics, we used lentiviral DNA barcoding, mtDNA variants and single cell gene expression profiling over 40 days after IR treatment. GSC cultures are versatile in their ability to support many in vitro protocols including high throughput screens as well as xenograft, organoid and other disease modeling protocols. They provide a simple cellular disease model for better understanding GBM biology, and for identifying new, potentially more effective GBM therapies and treatment regimens.

Keywords:  Cellular disease model; Cellular heterogeneity; Glioblastoma; Glioma stem cell; Proteogenomic subtyping; Radiation response

DOI:  https://doi.org/10.1038/s41598-025-33082-8
Nat Nanotechnol. 2025 Dec 26.

A biohybrid chiral hydrogel enhances preclinical postoperative glioblastoma therapy by multi-pronged inhibition of tumour stemness.

Tingting Cui, Sixue Chen, Siqin Liu, Xuegang Niu, Jun Wang, Rujiang Ao, Huilan Cai, Hongwei Huang, Meili Yu, Shanshan Peng, Xiaoyuan Chen, Lisen Lin.

Glioblastoma stem cells (GSCs), which exhibit resistance to multiple treatments, are a prominent driver of postoperative glioblastoma (GBM) relapse. Reducing the GSC population holds promise in GBM therapy but remains challenging due to the difficulty in coordinating the complex cytokine signalling programs and extracellular matrix characteristics that induce GSC expansion. Here we develop a biohybrid chiral hydrogel that allows intracavity implantation after GBM surgical debulking to comprehensively regulate GSC stemness, enhancing postoperative therapy. The hydrogel encapsulates GSC-membrane-coated nanoparticles that serve as potent decoys to broadly neutralize GSC-targeted pro-stemness and chemotaxis cytokines, allowing functional blocking and hydrogel infiltration of GSCs. Moreover, we showed that the D-chiral biohybrid hydrogel, in contrast to its L- and DL-chiral counterparts, further diminished the GSC stemness phenotype via D-chiral-geometry-regulated mechanotransduction pathways. In three orthotopic intracranial GBM models, the multi-pronged inhibition of GSC stemness enhanced gold-nanocluster-based hydrogel-scaffold-sensitized radioimmunotherapy, enabling the suppression of GBM relapse post-resection. This integrated regulation of biochemical and biophysical cues shows the potential for treating cancer-stem-cell-enriched malignancies.

DOI: https://doi.org/10.1038/s41565-025-02064-2
Lancet Oncol. 2026 Jan;pii: S1470-2045(25)00614-X. [Epub ahead of print]27(1): 45-56

Concurrent and adjuvant temozolomide for 1p/19q non-co-deleted anaplastic glioma (CATNON; EORTC study 26053-22054): final and exploratory analyses of a randomised, open-label, phase 3 trial.

Martin J van den Bent, Santoesha A Ghisai, Wolfgang Wick, Marc Sanson, Alba Ariela Brandes, Paul M Clement, Sara C Erridge, Michael A Vogelbaum, Anna K Nowak, Jean-François Baurain, Warren P Mason, Helen Wheeler, Emeline Tabouret, Sanjeev Gill, Matthew Griffin, Walter Taal, Roberta Rudà, Michael Weller, Catherine McBain, Jaap C Reijneveld, Roelien H Enting, Sébastien Tran, Thierry Lesimple, Martin Kocher, Anja Gijtenbeek, Elizabeth Lim, Ulrich Herrlinger, Peter Hau, Frederic Dhermain, Kenneth Aldape, Robert B Jenkins, Hendrikus Jan Dubbink, Johan M Kros, Pieter Wesseling, Youri Hoogstrate, Sarah Nuyens, Vassilis Golfinopoulos, C Mircea S Tesileanu, Thierry Gorlia, Pim French, Brigitta G Baumert.

BACKGROUND: The CATNON trial investigated the benefit of the addition of concurrent or adjuvant temozolomide to radiotherapy in individuals with anaplastic astrocytoma. We report the long-term follow-up of the study focusing on the individuals with isocitrate dehydrogenase (IDH) mutated (IDHmt) tumours.
METHODS: This randomised, open-label, phase 3 study in 137 institutions across Australia, Europe, and North America included participants aged 18 years or older with newly diagnosed 1p/19q non-co-deleted anaplastic gliomas and a WHO performance status of 0-2. Participants were randomly assigned (1:1:1:1) centrally using a minimisation technique to radiotherapy alone (59·4 Gy in 33 fractions), radiotherapy with concurrent oral temozolomide (75 mg/m2 per day), radiotherapy with adjuvant oral temozolomide (12 4-week cycles of 150-200 mg/m2 temozolomide given on days 1-5), or radiotherapy with both concurrent and adjuvant temozolomide. Participants were stratified by institution, WHO performance status score, age, 1p loss of heterozygosity, the presence of oligodendroglial elements on microscopy, and MGMT promoter methylation status. The primary endpoint was overall survival adjusted by stratification factors at randomisation in the intention-to-treat population. The eighth amendment of the study protocol (June 27, 2011) incorporated analysis of IDH mutational status into the study. We report the intention-to-treat analysis and the exploratory analysis within the population of participants with astrocytoma with an IDH mutation. As the safety data have been published previously, no safety data are reported. This trial is registered with ClinicalTrials.gov, NCT00626990, and is completed.
FINDINGS: Between Dec 4, 2007, and Sept 11, 2015, 1407 participants were registered and 751 participants were randomly allocated, 444 of whom were diagnosed with an IDHmt tumour. After a median follow-up for overall survival of 10·9 years (IQR 9·5-12·7), in the intention-to-treat population, adjuvant temozolomide improved overall survival compared with no adjuvant temozolomide (hazard ratio [HR] 0·65 [95% CI 0·54-0·77]), but concurrent did not compared with no concurrent temozolomide (HR 0·91 [0·76-1·08]). In univariable analysis of the participants with an IDHmt tumour, concurrent temozolomide had no statistically significant effect on overall survival (median 9·7 years [8·2-12·5] vs 7·2 years [6·2-9·4]; HR 0·81 [0·63-1·04]), but median overall survival was 12·5 years (95% CI 9·4-15·0) with adjuvant temozolomide compared with 6·0 years (5·1-7·2) with no adjuvant temozolomide (HR 0·54 [0·42-0·69]). No benefit of temozolomide, neither concurrent nor adjuvant, was observed in participants with IDH wild-type tumours. Methylation-based subtyping and several DNA alterations (eg, amplification of PDGFRA and CDK4, homozygous deletion of CDKN2A, and total copy number variation) were associated with worse outcome, none of which was predictive for benefit to temozolomide.
INTERPRETATION: Long-term follow-up confirms that radiotherapy followed by 12 cycles of adjuvant temozolomide without concurrent temozolomide during radiotherapy improves survival for individuals with aggressive IDHmt astrocytoma.
FUNDING: MSD.

DOI: https://doi.org/10.1016/S1470-2045(25)00614-X
Cell Mol Immunol. 2025 Dec 23.

C/EBPβ-induced alternative splicing of RCAN1 generates a potent TCR-T target in mesenchymal glioblastoma.

Zujian Xiong, Qinglin Kong, Bhuvitha Chagantipati, Amelia Stepniak, Ambika P Jaswal, Chaim T Sneiderman, Yuanyuan Han, Sydney A Jackson, Rebecca A Raphael, Wei Zhang, Muzi Li, Yapeng Chao, Bin Qin, Zeynep Dulkadir, Lance Schwegman, Yihao Zhang, Chloe Kuminkoski, Megan A Mahlke, Poulomi Nath, Baoli Hu, Pascal O Zinn, Megan Mantica, Sameer Agnihotri, Yael Nechemia-Arbely, Ian F Pollack, Lora H Rigatti, Thomas G Forsthuber, Xuejun Li, Itay Raphael, Gary Kohanbash.

  Glioblastoma (GBM) is an aggressive brain tumor with limited treatment options and a dismal prognosis. While immunotherapy has shown promise in treating some solid tumors, the treatment of GBM has been mostly unsuccessful because of a lack of targetable tumor antigens and high tumor heterogeneity. Here, we report RCAN1-4 as a novel tumor antigen derived from alternative splicing induced by the transcription factor C/EBPβ. Both C/EBPβ and RCAN1-4 are highly expressed in GBM and glioma stem cells as mesenchymal subtype hallmarks. We report an immunogenic HLA-A24-specific splicing junction epitope within exon 4 and exon 5 that is unique to RCAN1-4. This epitope was validated for its ability to stimulate T cell responses in HLA-A24+ donors and GBM patients, leading us to identify RCAN1-4-reactive T cell receptors (TCRs) for the construction of TCR-engineered T cells (TCR-T cells). Functional studies of TCR-Ts demonstrated the in vitro and in vivo killing of RCAN1-4pos GBM tumor cells, highlighting its potential as an immunotherapeutic target in mesenchymal GBM.

Keywords:  Alternative splicing; Antigen detection; GBM; RCAN1; TCR-T

DOI:  https://doi.org/10.1038/s41423-025-01360-0
J Clin Invest. 2025 Dec 23. pii: e195189. [Epub ahead of print]

Mismatch repair deficiency drives malignant progression and alters the tumor immune microenvironment in glioblastoma models.

Montserrat Puigdelloses Vallcorba, Nishant Soni, Seung-Won Choi, Kavita Rawat, Tanvi Joshi, Sam Friedman, Alice Buonfiglioli, Angelo Angione, Zhihong Chen, Gonzalo Piñero, Gabrielle Price, Mehek Dedhia, Raina Roche, Emir Radkevich, Anne M Bowcock, Deepti Bhatt, Winfried Edelmann, Robert M Samstein, Timothy E Richardson, Nadejda M Tsankova, Alexander M Tsankov, Ranjit S Bindra, Raul Rabadan, Juan C Vasquez, Dolores Hambardzumyan.

  Mutations in DNA mismatch repair (MMR) pathway genes (MSH2, MSH6, MLH1, and PMS2) are linked to acquired resistance to temozolomide (TMZ) and high tumor mutation burden (TMB) in high-grade gliomas (HGG), including glioblastoma (GBM). However, the specific roles of individual MMR genes in the initiation, progression, TMB, microsatellite instability (MSI), and resistance to TMZ in glioma remain unclear. Here, we developed de novo mouse models of germline and somatic MMR-deficient (MMRd) HGG. Surprisingly, loss of Msh2 or Msh6 does not lead to high TMB, MSI, nor confer response to anti-PD-1 in GBM. Similarly, human GBM shows discordance between MMR gene mutations and TMB/MSI.Germline MMRd leads to promoted progression from low-grade to HGG and reduced survival compared to MMR-proficient (MMRp) tumor-bearing mice. This effect is not tumor cell intrinsic but is associated with MMRd in the tumor immune microenvironment, driving immunosuppressive myeloid programs, reduced lymphoid infiltration, and CD8+ T cell exhaustion. Both MMR-reduced (MMRr) and MMRd GBM are resistant to temozolomide (TMZ), unlike MMRp tumors. Our study shows that KL-50, a imidazotetrazine-based DNA targeting agent inducing MMR-independent cross-link-mediated cytotoxicity, was effective against germline and somatic MMRr/MMRd GBM, offering a potential therapy for TMZ-resistant HGG with MMR alterations.

Keywords:  Brain cancer; Cell biology; DNA repair; Immunology; Immunotherapy; Neuroscience; Oncology

DOI:  https://doi.org/10.1172/JCI195189
Microb Cell. 2025 ;12 290-298

The dual-site agonist for human M2 muscarinic receptors Iper-8-naphtalimide induces mitochondrial dysfunction in Saccharomyces cerevisiae.

Angela Cirigliano, Antonia Amelina, Elena Passarini, Alessandra Ricelli, Nicole Balasco, Mattia Mori, Bruno Botta, Maria Egle De Stefano, Claudio Papotto, Claudia Guerriero, Ada Maria Tata, Teresa Rinaldi.

  Glioblastoma is a malignant astrocytic tumor of the brain. A significantly decrease of glioblastoma cell proliferation and survival can be achieved by activating the M2 muscarinic acetylcholine receptor (a G protein-coupled receptor, or GPCR) with two agonist molecules, the orthosteric agonist Arecaidine Propargyl Ester (APE) and the dual-steric agonist Iper-8-naphthalimide (N-8-Iper). In glioblastoma cells, these agonists caused mitochondrial damage and an altered lipid profile. To characterize the mitochondrial dysfunction induced by the muscarinic agonists, we tested APE and N-8-Iper in S. cerevisiae, a yeast model system specifically suitable to study the activity of molecules of pharmaceutical interest on mitochondria. N-8-Iper, but not APE, induced mitochondrial dysfunction in S. cerevisiae cells in a time- and concentration-dependent manner. These results suggest that the agonist N-8-Iper on glioblastoma cell cultures has a direct effect on mitochondrial function. Moreover, since GPCRs are evolutionarily conserved from yeast to humans, these results confirm that the yeast system is a suitable model for studying human GPCRs.

Keywords:  Glioblastoma; M2 muscarinic receptor; dualsteric agonist; ergosterol; mitochondrial DNA; modeling in S. cerevisiae; orthosteric agonist

DOI:  https://doi.org/10.15698/mic2025.12.862
Nat Genet. 2025 Dec 22.

Patterns of hypermutation shape tumorigenesis and immunotherapy response in mismatch-repair-deficient glioma.

Nicholas R Fernandez, Yuan Chang, Nuno M Nunes, Jose R Dimayacyac, Adrian Levine, Amit Ringel, Logine Negm, Ayse Bahar Ercan, Julian M Hess, Olfat Ahmad, Caitlin Lee, Lucie Stengs, Vanessa Bianchi, Melissa Edwards, Sheradan Doherty, Jiil Chung, Liana Nobre, Julie Bennett, Andrew J Dodgshun, David T W Jones, Stefan M Pfister, Anita Villani, David Malkin, Vijay Ramaswamy, Annie Huang, Eric Bouffet, Melyssa Aronson, Peter B Dirks, Adam Shlien, Gad Getz, Yosef E Maruvka, Birgit Ertl-Wagner, Cynthia Hawkins, Anirban Das, Uri Tabori.

Primary mismatch-repair-deficient high-grade gliomas (priMMRD-HGG) are lethal tumors characterized by hypermutation, resistance to chemoradiation and variable response to immunotherapy. To investigate the mechanisms governing the emergence of driver mutations and their impact on gliomagenesis and patient outcomes, we analyzed genomic and clinical data from 162 priMMRD-HGG. Here we identified three subgroups defined by secondary driver mutations in replicative DNA polymerases or IDH1. These subgroups converge on glioma drivers through distinct combinations of genomic instability-generating mechanisms, displaying an inverse correlation between point mutations and copy number alterations. MMRD signatures drive the emergence of specific mutations in TP53 and IDH1, notably excluding common pediatric glioma drivers. Global hypomethylation stratifies priMMRD-HGG into a unique methylation cluster. DNA-polymerasemut priMMRD-HGG exhibit ultrahypermutation, an immune-hot microenvironment and immunotherapy responsiveness, whereas IDH1mut priMMRD-HGG are immune-cold and immunotherapy resistant. MMRD-driven gliomagenesis defines the role of nonrandom mutagenesis patterns in cancer development, providing frameworks for targeted and immune-therapeutics.

DOI: https://doi.org/10.1038/s41588-025-02420-x
bioRxiv. 2025 Dec 16. pii: 2025.12.12.693499. [Epub ahead of print]

Molecular profiling of glioblastoma-derived extracellular vesicles identifies small nucleolar RNAs as candidate liquid biomarkers for radiation-induced senescence.

Valerie DeLuca, Nathaniel Hansen, Priya Digumarti, Nanyun Tang, Karen Fink, George Snipes, Patrick Pirrotte, Michael Berens.

Radiation-induced senescence (RIS) in glioblastoma (GBM) is an undesirable cell fate that inhibits tumor cell death and supports resistance and outgrowth. While senescence-targeting drugs are promising adjuvants, their clinical application will require proper patient selection based on post-treatment RIS burden. Current methods to evaluate senescence, however, are tissue-based, and given GBM's difficult anatomical location, post-treatment biopsies are impractical. Therefore, novel and less invasive biomarkers for TIS are urgently needed. To this end, we aimed to identify candidate extracellular vesicle (EV) liquid biomarkers for TIS by profiling senescence-associated cargo changes within GBM EVs. Using a panel of GBM patient-derived cell lines, we show that RIS is the primary functional state following radiation exposure and is associated with significant alterations in the cargo of senescent-derived EVs (senEVs). In particular, senEV transcriptomes have an increased abundance of senescence-associated RNA species and enrichment of senescence-associated gene sets. Most striking, however, was that senEVs are most differentiated by the significant enrichment of a panel of snoRNAs. This signature was conserved in 4/5 GBM models of RIS and was validated by qRT-PCR. Further analysis by mass spectrometry revealed that snoRNAs are likely co-packaged with their associating proteins, as senEVs had concurrent increases in these binding partners. Finally, in a preliminary patient cohort comparing plasma EVs obtained prior to surgery to those obtained after completion of their radiation therapy, we identified increased senescence-associated RNA such as CDKN2B and GLB1 and the snoRNA SNORA49 in post-radiation EVs. Altogether, this data suggests that senEV RNA species, and particularly snoRNAs, are a promising analyte for RIS-biomarker development. With further study, this work may open avenues for a companion diagnostic for senotherapeutics.

DOI: https://doi.org/10.64898/2025.12.12.693499
Sci Rep. 2025 Dec 22.

Navitoclax acts synergistically with irradiation to induce apoptosis in preclinical models of H3K27M-altered diffuse midline glioma.

Ashley Vardon, Scott Haston, Hiba Hamdi, Grace Cooksley, Romain Guiho, Diana Carvalho, Rebecca Carter, Jessica Katherine Rowena Boult, Daniel Gharai, Ielyaas Cloete, James Grey, John Apps, Daohong Zhou, Guangrong Zheng, Ramón Martínez-Máñez, Mark Francis Lythgoe, Laura Kate Donovan, Angel Montero Carcaboso, Owen Williams, Ying Hong, Paula Alexandre, Jesus Gil, Jamie Adam Dean, David Michod, Chris Jones, Darren Hargrave, Juan-Pedro Martinez-Barbera.

  Diffuse midline gliomas (DMGs) with histone H3K27M mutations represent a devastating paediatric brain cancer characterised by abysmal prognosis and limited treatment options. The only approved treatment is radiotherapy (RT), but most of the tumours relapse with fatal consequences. The effects of RT remain unknown because patients are not biopsied during treatment. Here, we sought to investigate whether irradiation leads to senescence induction in DMG and explore the efficacy of senolytics. We show that ionising radiation induces senescence in various H3K27M-altered DMG cell lines. Senescence induction is demonstrated by immunocytochemistry, RNA-sequencing and analysis of SASP factors by ELISA. Through testing several senolytic compounds, we identify that Bcl2 family inhibitors (e.g., Navitoclax) act as potent senolytics, driving senescent DMG cells into apoptosis, primarily via Bcl-xL inhibition. Reinforcing these findings, proteolysis-targeting chimeras (PROTACs) targeting Bcl-xL and galacto-conjugated Navitoclax (Nav-Gal) also exhibit strong senolytic activity against senescent DMG cancer cells. Finally, we show that a combination of irradiation with Navitoclax enhances cancer cell apoptosis in an orthotopic xenograft DMG model. Together, the data demonstrate that ionising irradiation leads to senescence induction in H3K27M-altered human DMG cell lines, making them particularly sensitive to apoptosis through Bcl-xL inhibition.

Keywords:  BH3-mimetics; Bcl-xL; Cellular senescence; H327M-altered diffuse midline glioma; Senolytic therapy

DOI:  https://doi.org/10.1038/s41598-025-32676-6