bims-malgli 2026-09-27 papers

Issue of 2026–09–27
seven papers selected by
Oltea Sampetrean, Keio University

Neuro Oncol. 2026 Sep 25. pii: noag200. [Epub ahead of print]

Glioma and ependymoma through the lens of brain development, stem cells, and plasticity.

Costanza Lo Cascio, Antoni Martija, Mariella G Filbin, Aparna Bhaduri.

Brain tumors are increasingly understood as having components of a development organization in which malignant cells leverage neural progenitor programs, lineage hierarchies, and circuit interactions that normally shape the developing brain. This review examines how these principles inform the biology of ependymoma and gliomas across the age spectrum, including H3 K27-altered diffuse midline glioma, H3 G34-mutant diffuse hemispheric glioma, IDH-mutant glioma, and glioblastoma. We highlight how tumor identity reflects developmental timing, regional context, and cell-of-origin competence, while also emphasizing that malignant cells can acquire plasticity beyond their normal counterparts. Across entities, single-cell, spatial, lineage-tracing, and organoid studies reveal progenitor-like compartments that sustain tumor growth, generate heterogeneous malignant states, and interact dynamically with the neural and immune microenvironment. Cancer neuroscience further extends this developmental framework by showing that neuronal activity, synaptic input, and neuromodulatory signaling can regulate tumor proliferation, migration, epigenetic state, and therapeutic response. Together, these findings argue that brain tumors should be viewed not as disorganized cellular masses but as aberrant developmental systems. Defining the developmental dependencies and circuit vulnerabilities of malignant progenitor states may enable more precise therapies that target tumor biology while preserving essential brain function.

Keywords: development in brain cancer; glioblastoma; pediatric brain cancer; plasticity; stem cells

DOI: https://doi.org/10.1093/neuonc/noag200

Oncogene. 2026 Sep 20.

Beyond the blood-brain barrier: humanised mice, the missing link in glioblastoma research.

Reza Shirazi Nia, Jian Lu, Daniel De Vega, Niloufar Poudine, Chaoyue Pan, Fengqi Zhou, Jianxiong Ji, Georgios Giamas.

Glioblastoma (GBM) remains a major challenge in neuro-oncology, associated with a high rate of mortality despite decades of intensive research and therapeutic advancements, underscoring the urgent need for innovative preclinical platforms that can more accurately recapitulate the biological and pathological features of human disease. While conventional animal models have contributed to our understanding of GBM biology and the evaluation of treatment efficacy, they fail to capture the full complexity and heterogeneity of the tumour microenvironment (TME). Ex vivo models are associated with certain advantages in this context; however, they can not mirror the complex dynamic and multicellular interactions present in living organisms, particularly the critical treatment barriers unique to the central nervous system: the blood-brain barrier (BBB), blood-cerebrospinal fluid barrier (BCSFB) and blood-meningeal barrier (BMB). In response to these limitations, humanised mouse models have emerged as an advanced platform capable of faithfully mimicking the molecular, pathological and immunological features of human GBM. These models enable the replication of complex in vivo crosstalk between the immune system and the TME, while preserving the relevant treatment barriers that govern drug delivery to the brain. Accumulating evidence indicates that humanised mouse models closely reproduce the infiltration of human immune components into the TME, enabling the study of clinically relevant interactions that contribute to therapeutic resistance and treatment failure in GBM. This review aims to provide a comprehensive and systematic overview of the currently employed humanised mouse models in GBM research, highlighting their applications and comparative advantages. Finally, we evaluate the opportunities and challenges associated with each model and discuss future directions to increase the translational relevance and predictive power of preclinical GBM research. Humanised mouse models provide a valuable translational platform combining the human immune system and PDX orthotopic engraftment. Compared to conventional models and ex vivo models, these models can reproduce the complex cross-talk between tumour cells and the immune system, tumour heterogeneity, immunosuppressive TME, as well as complex in vivo interactions such as brain-specific barriers, including BBB, BCSFB and BMB. Future implementation of the human gut microbiome in these models has the potential to further increase translational relevance and precision in GBM research. Created in BioRender.com.

DOI: https://doi.org/10.1038/s41388-026-03989-1

Res Sq. 2026 Sep 18. pii: rs.3.rs-10976328. [Epub ahead of print]

Microenvironment-derived acetylated amino acids promote glioblastoma treatment resistance.

Rapid repair of genotoxic therapy induced DNA damage mediates treatment resistance in glioblastoma (GBM). The role of non-malignant cell types in the tumor microenvironment in accelerating DNA repair in neoplastic cells is poorly understood. Using spatial transcriptomics, immunofluorescence, metabolomics, patient tissues and preclinical models, we show that tumor associated macrophages (TAMs) in GBM promote DNA repair and treatment resistance in neoplastic cells through the secretion of acetylated amino acids. These acetylated amino acids are consumed by GBM cells, leading to enhanced acetyl Co-A levels, histone acetylation and nucleotide synthesis. Interrupting histone acetylation via inhibition of the acetyltransferase KAT5 breaks these metabolic links and reverses the protective capacity of microenvironment-derived acetylated amino acids and TAMs. Blocking the exchange of acetylated amino acids and their downstream effects is a potential strategy for the treatment of GBM.

DOI: https://doi.org/10.21203/rs.3.rs-10976328/v1

Nat Commun. 2026 Aug 21. pii: 10042. [Epub ahead of print]17(1):

Metabolic licensing of quiescent glioblastoma activation and immune evasion via astrocyte-mitochondria shuttle.

Hongrui Zhu, Li Wang, Qi Wu, Yanwei Yu, Mengmeng Yang, Youqiong Ye, Wenchao Zhou, Jiabei Wang, Xuedan Sun, Sheng Wang, Qingsong Hu.

Reactivating quiescent tumor cells at the invasive margin are either eliminated by immune surveillance or expand through immune escape. The mechanisms underpinning phenotypic plasticity driving expansion leading to therapeutic resistance, dissemination, and recurrence remain elusive. Here we establish a metabolic licensing paradigm wherein reactive astrocytes awaken dormant glioblastoma cells and simultaneously confer immune evasion through intercellular mitochondrial transfer. Astrocyte-derived mitochondria, enriched with the one carbon metabolism enzyme SHMT2, deliver functional metabolic units that reprogram recipient glioma cells. This shuttled cargo fuels S adenosylmethionine production, driving m⁶A RNA methylation and release of paused RNA polymerase II over a specific set of genes. Ribosome biogenesis and focal adhesion pathways are selectively upregulated consequently, which enables rapid proliferation and immune resistance of tumour cells. Genetic ablation of astrocytic Shmt2 or pharmacological blockade of mitochondrial transfer suppresses quiescent cell reactivation and delays tumor progression. Our findings thus establish the astrocyte-mitochondria shuttle as a core vulnerability in glioblastomas, linking metabolic crosstalk to epitranscriptomic control of reactivation and immune escape.

DOI: https://doi.org/10.1038/s41467-026-76828-2

Clin Med (Lond). 2026 Sep 20. pii: S1470-2118(26)00092-8. [Epub ahead of print] 100643

Updates to contemporary care of glioblastoma.

Bernadeth Lyn C Piamonte, Wiley Gillam, Megan E H Still, Ashley P Ghiaseddin, Matt Williams, Sara Elsharkawy, Christine Lu-Emerson.

Glioblastoma is the most common and aggressive primary malignant brain tumor in adults. Over the years, the diagnostic criteria have been refined, incorporating molecular markers with histology to reflect the underlying tumor biology. Advances in genomics and molecular techniques are currently focused on trying to subcategorize the tumors for potential prognostic and clinical purposes. Treatment consists of multiple modalities including surgery, radiation, and systemic treatments. While targeted therapy traditionally has not been effective due to the heterogeneity of the tumor, fusions and certain mutations may benefit from specific targeted therapies. Tumor treating fields is a novel treatment that has shown survival benefit in newly diagnosed glioblastoma, and ongoing trials are underway to capitalize on its mechanism. Finally, special consideration should be given to palliative care in light of the high morbidity and mortality associated with glioblastoma. In particular, the balance of aggressive care and quality of life must be weighed in the geriatric population though contemporary studies have shown good tolerance for a hypofractionated course of chemoradiation.

Keywords: Glioblastoma; elderly; integrated diagnosis; treatment; updates to care

DOI: https://doi.org/10.1016/j.clinme.2026.100643

Cancer Res Commun. 2026 Sep 21.

Integrated genetic screening identifies FEN1 as a selective vulnerability and temozolomide resistance mediator in glioblastoma stem cells.

Glioblastoma (GBM) is an aggressive brain tumor characterized by therapy resistance and recurrence. Glioblastoma stem cells (GSCs) are key drivers of tumor maintenance, therapeutic resistance, and relapse, but targeting them remains clinically elusive due to their overlap with normal neural stem cells (NSCs) and a lack of actionable vulnerabilities. To identify selective vulnerabilities in GSCs, we performed genome-wide CRISPR-Cas9 loss-of-function screening across patient-derived GSC models under standard-of-care treatment conditions. We identified flap endonuclease 1 (FEN1), a key enzyme in DNA replication and base excision repair, as an essential gene for GSC survival, with enhanced dependency in the context of temozolomide (TMZ) treatment. Genetic knockdown of FEN1 impaired GSC proliferation and self-renewal and extended survival in a patient-derived xenograft model. Pharmacologic inhibition of FEN1 using a small-molecule inhibitor revealed selective cytotoxicity in highly aggressive and recurrent GBM models, while sparing NSCs. Notably, FEN1 inhibition synergized with TMZ to induce DNA double-strand breaks and potentiate cell death only in a subset of GSCs sensitive to FEN1 inhibition. Mechanistically, single-cell transcriptomics revealed that FEN1 expression correlates with programs linked to proliferation, stemness, and DNA damage repair, underscoring its role in maintaining the treatment-refractory phenotype. Our findings identify FEN1 as a selective vulnerability in aggressive, proliferative GSCs. FEN1 inhibition not only impairs GSC viability but also restores sensitivity to TMZ in treatment-resistant models, offering a strategy for salvage therapy in recurrent GBM. These results support the development of FEN1-targeted therapies and lay the foundation for a biomarker-guided approach to overcome chemoresistance in GBM.

DOI: https://doi.org/10.1158/2767-9764.CRC-26-0150

bioRxiv. 2026 Sep 16. pii: 2026.06.17.731637. [Epub ahead of print]

Oncohistone inhibition reshapes tumor-microenvironment communication in Diffuse Midline Glioma (DMG).

Niloofar Khairkhah, Mostafa M H Ibrahim, Sienna L Galban, Megan Faunce, Lily Rober, Carlen Baker, Robert Doherty, Rodrigo Cartaxo, Carl Koschmann, Yue Zhao, Stefanie Galban.

Background: Diffuse midline glioma (DMG) is a lethal pediatric brain tumor driven by the H3K27M oncohistone, which disrupts epigenetic regulation and promotes tumor proliferation. While prior studies show that H3K27M is essential for tumor initiation, its role in established tumors, tumor microenvironment (TME) regulation, and therapeutic response remain unclear.
Methods: Here, we developed inducible and reversible H3.3K27M and H3.1K27M cell and mouse models to study oncohistone-dependent effects and the immune/stromal microenvironment. We generated a tetracycline-inducible PiggyBac-based oncohistone expression cassette in patient- and murine-derived models and validated inducible and reversible H3K27M expression.
Results: Re-expression of H3K27M in knockout cells induced morphological changes and suppressed astrocytic markers. Chromatin accessibility profiling revealed locus-specific differences between ON, OFF, and OFF-ON, including changes at loci associated with immune regulation and tumor-microenvironment interactions. Single-cell RNA sequencing demonstrated that the oncohistone reshapes the TME. H3K27M expression promotes tumor-neuron interactions, enhances neuronal excitability, excitatory/inhibitory imbalance, and synaptic connectivity that likely supports tumor proliferation. These effects are associated with increased glutamatergic signaling and enhanced tumor-neuron coupling through glutamate transport and receptor pathways, including EAAT1 ( SLC1A3 ) and AMPARs ( GRIA3 ). Conversely, H3K27M inhibition reduces neuronal excitation, disrupts tumor-associated signaling, and partially restores neuron-neuron and neuron-immune communications. These findings identify H3K27M as a key driver of excitatory neuron-to-tumor coupling and immunosuppression in DMG.
Conclusions: Overall, our findings demonstrate that H3K27M extensively reshapes TME in DMG and support direct oncohistone targeting as a potential therapeutic strategy, including potential CRISPR-based or small-molecule approaches for patients with H3K27M-mutant DMG.
Key Points: We developed inducible and reversible H3K27M DMG models to investigate the role of H3K27M in the tumor microenvironment.H3K27M promotes tumor-neuron communication, while its inhibition disrupts these interactions, supporting H3K27M-targeted therapies for DMG.
Importance of Study: Diffuse midline glioma (DMG) remains one of the deadliest pediatric brain tumors, with limited effective treatment options and poor patient survival. Although the H3K27M oncohistone is recognized as a key driver of tumor initiation, its role in maintaining tumor progression and shaping the tumor microenvironment is unclear. In this study, we developed inducible and reversible H3.3K27M and H3.1K27M murine and patient-derived DMG cell- and mouse-models that enabled precise control of the oncohistone expression. Using these models, we demonstrate that H3K27M actively promotes tumor-neuron interactions, neuronal excitability, and glutamatergic signaling pathways that support tumor growth. Importantly, inhibition of H3K27M disrupted these tumor-associated signaling networks and partially restored neuron- immune communication within the tumor microenvironment. Together, these findings demonstrate that H3K27M extensively reshapes the tumor microenvironment in these Diffuse Midline Gliomas and provides strong rationale for directly targeting the oncohistone as a therapeutic strategy for patients with H3K27M-mutant DMG.

DOI: https://doi.org/10.64898/2026.06.17.731637