bims-malgli 2025-10-19 papers

bims-malgli

Biomed News

on Biology of malignant gliomas

Issue of 2025–10–19
ten papers selected by
Oltea Sampetrean, Keio University

Par6/SOX2 interact to modulate stemness maintenance in glioma by regulating the EGFR/PI3K/AKT signaling cascade.
A non-local diffusion magnetic resonance imaging tract density biomarker to stratify, predict, and interpret survival rates in human glioblastoma.
BEHAV3D Tumor Profiler to map heterogeneous cancer cell behavior in the tumor microenvironment.
T cell immunity in glioma and potential implications for immunotherapy: a systematic review.
CRISPR screen reveals SOX2 as a critical regulator of CD133 and cellular stress response in glioblastoma.
Now you serine, now you don't.
Glioma neuron symbiosis: a hypothesis.
BRD4 inhibition sensitizes glioblastoma to radiotherapy by suppressing super-enhancer-driven COL1A1.
Phase I/II and Window-of-Opportunity Study of Pamiparib and Metronomic Temozolomide for Recurrent IDH Mutant Gliomas.
CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2018-2022.

Oncogene. 2025 Oct 11.

Par6/SOX2 interact to modulate stemness maintenance in glioma by regulating the EGFR/PI3K/AKT signaling cascade.

Ting Yang, Yan Zeng, Ya Li, Yishan Huang, Xin Meng, Chunjiao Lu, Chenchen Zhu, Pei Liu, Jing Liu, Shaocai Hao, Juanjuan Luo, Wei Cui, Xiaojun Yang.

Glioma stem cells (GSCs) are a primary factor contributing to the failure of glioma treatment and lead to a poor prognosis for patients with glioma. However, the biological functions and mechanisms involved in regulating stemness maintenance in GSCs are not well understood. Here, we investigated the potential regulatory effects of Par6 on stemness maintenance in GSCs. Our data revealed high expression of Par6 in glioma specimens is usually accompanied by a poor prognosis. Further study indicated Par6 expression might be involved in stemness maintenance of GSCs by directly binding to SOX2 in glioma cells. In contrast, the blockade of Par6/SOX2 interaction with a specific inhibitory peptide (Par6i-P1) significantly suppressed the stemness maintenance of GSCs. Gene manipulation results showed the combination of Par6 and SOX2 promoted stemness maintenance in a complementary manner. Mechanistically, we identified PI3K/AKT signaling pathway as a downstream target of EGFR, which is also transcriptionally regulated by SOX2 in glioma cells. Moreover, a clinical study indicated the coexpression of Par6 and SOX2 predicted poor outcomes for glioma patients, suggesting the Par6/SOX2 interaction might trigger the regulation of stemness maintenance through activating EGFR/PI3K/AKT signaling pathway in glioma. Furthermore, comparing with the scrambled peptide control, the tumorigenicity assay and immunohistochemistry indicated that targeting the Par6/SOX2 interaction might effectively mitigate GSC-mediated chemotherapy resistance in temozolomide (TMZ) treatment, and improve the malignancy and prognosis in mice orthotopically transplanted with GBM. Together, these findings reveal a novel mechanism by which the Par6/SOX2 interaction contributes to the maintenance of stemness in GSCs and may serve as a promising therapeutic target for improving the prognosis of glioma patients.

DOI: https://doi.org/10.1038/s41388-025-03595-7
Neuro Oncol. 2025 Oct 11. pii: noaf234. [Epub ahead of print]

A non-local diffusion magnetic resonance imaging tract density biomarker to stratify, predict, and interpret survival rates in human glioblastoma.

Joan Falcó-Roget, Gianpaolo Antonio Basile, Anna Janus, Sara Lillo, Letterio Salvatore Politi, Jan K Argasinski, Alberto Cacciola.

   BACKGROUND: Glioblastoma (GBM) is a lethal tumor, actively growing and invading neighboring neural tissue. GBMs appear functionally connected to distributed and spatially distant regions rather than representing an isolated and passive lesion disrupting the brain circuitry. Moreover, increasing evidence suggests that white matter serves as the morphological substrate for GBM to progress and migrate to distant areas in the human brain.
METHODS: We hypothesized that the subset of white matter tracts intersecting the tumors depicts the physical substrate for large-scale neuron-glioma interactions and would therefore inform prognosis. Using normative models, we design, analyze, interpret, and test a Lesion-Tract Density Index (L-TDI) marker that considers the distributed white matter pathways interacting with the tumor in two independent cohorts of N=367 and N=496 patients, respectively.
RESULTS: First, we show that the average tract density within this white matter map robustly stratifies survival rates due to widespread white matter involvement. Second, we demonstrate why tract density-based markers offer critical and necessary insights into the morphology, location, and evolution of human GBM by proving how the proposed L-TDI implicitly considers tumor volume, white matter density, and location. We provide further evidence that the non-uniform distribution of GBMs and their differential prognosis emerge from white matter morphology. Third, we validate the L-TDI marker with multiple Cox survival models and analyze its contribution in relation to other covariates of interest (e.g., MGMT promoter methylation). Lastly, by using a simple logistic model, we predict patient death at 12 months with balanced accuracies of 68% and 65%, and areas under the curve of 0.74 and 0.73 when training and testing in separate and independent cohorts.
CONCLUSIONS: Overall, we offer a concrete implementation of the emerging paradigm that views GBM not as a focal lesion, but as a network disease shaped by its complex interactions with distant brain regions.

Keywords:  Brain connectome; Diffusion tractography; Glioblastoma; Survival prediction

DOI:  https://doi.org/10.1093/neuonc/noaf234
Elife. 2025 Oct 15. pii: RP102097. [Epub ahead of print]13

BEHAV3D Tumor Profiler to map heterogeneous cancer cell behavior in the tumor microenvironment.

Emilio Rios-Jimenez, Anoek Zomer, Raphael Collot, Mario Barrera Román, Sandra F Archidona, Hendrikus Ariese, Ravian van Ineveld, Michiel Kleinnijenhuis, Nils Bessler, Hannah Johnson, Caleb A Dawson, Anne Rios, Maria Alieva.

  Intravital microscopy (IVM) enables live imaging of animals at single-cell level, offering essential insights into cancer progression. This technique allows for the observation of single-cell behaviors within their natural 3D tissue environments, shedding light on how genetic and microenvironmental changes influence the complex dynamics of tumors. IVM generates highly complex datasets that often exceed the analytical capacity of traditional uni-parametric approaches, which can neglect single-cell heterogeneous in vivo behavior and limit insights into microenvironmental influences on cellular behavior. To overcome these limitations, we present BEHAV3D Tumor Profiler (BEHAV3D-TP), a computational framework that enables unbiased single-cell classification based on a range of morphological, environmental, and dynamic single-cell features. BEHAV3D-TP integrates with widely used 2D and 3D image processing pipelines, enabling researchers without advanced computational expertise to profile cancer and healthy cell dynamics in IVM data from mouse models. Here, we apply BEHAV3D-TP to study diffuse midline glioma (DMG), a highly aggressive pediatric brain tumor characterized by invasive progression. By extending BEHAV3D-TP to incorporate tumor microenvironment (TME) data from IVM or fixed correlative imaging, we demonstrate that distinct migratory behaviors of DMG cells are associated with specific TME components, including tumor-associated macrophages and vasculature. BEHAV3D-TP enhances the accessibility of computational tools for analyzing the complex behaviors of cancer cells and their interactions with the TME in IVM data.

Keywords:  cancer biology; cell migration; computational biology; confocal microscopy; image analysis; mouse; systems biology

DOI:  https://doi.org/10.7554/eLife.102097
Neuro Oncol. 2025 Oct 17. pii: noaf236. [Epub ahead of print]

T cell immunity in glioma and potential implications for immunotherapy: a systematic review.

Rosa Luning, Pim J French, Wouter J F Vanbilloen, Lisa Dobber, Levi Van Hijfte, Raoull Hoogendijk, Martin J Van Den Bent, Reno Debets, Marjolein Geurts.

   BACKGROUND: T cell-based immunotherapies have had limited success in glioma thus far. Here, we evaluate the literature on abundance, spatial distribution and phenotypical characteristics of T cells in the tumor micro-environment (TME) of IDH-mutant and IDH-wildtype glioma, with the aim to understand how these measures relate to immunotherapy resistance and to aid the development of immunotherapies for glioma.
METHODS: Medline, Embase, Web of Science Core Collection, Google Scholar and the Cochrane Central Register of Controlled Trials were systematically searched up to May 6th, 2025. Out of 4,303 articles screened, 85 studies examining T cell immunity in human glioma were selected. We collected information about tumor subtype, grade, methods, T cell abundance, spatial distribution, phenotypes and prognostic significance.
RESULTS: T cells are present in the glioma TME, but at heterogeneous and generally low densities, especially in IDH-mutant glioma. T cell abundance increases with higher WHO grade and upon recurrence. T cells cluster around blood vessels, especially in IDH-mutant glioma. Glioma-infiltrating T cells largely display a late-differentiated phenotype (CD45RA-CCR7-C62L-), expressing markers that signify sustained antigen activation and exhaustion (PD-1, CTLA-4, TIM-3, LAG-3, CD39 and TIGIT). This phenotype coincides with decreased anti-tumor cytotoxicity and is spatially enriched in the myeloid-rich, hypoxic tumor core. Prognostic significance remains controversial.
CONCLUSIONS: T cells in glioma are scarce, generally fully differentiated and functionally inert. Understanding and reinvigorating the deficient T cell response will be essential for successful immunotherapies. Future research should incorporate functional and spatial immune profiling to optimize and personalize immunotherapeutic strategies for glioma patients.

Keywords:  Glioma; T cells; TME; immunotherapy; phenotype

DOI:  https://doi.org/10.1093/neuonc/noaf236
Sci Rep. 2025 Oct 16. 15(1): 36228

CRISPR screen reveals SOX2 as a critical regulator of CD133 and cellular stress response in glioblastoma.

Neil Savage, Etienne Danis, Chirayu R Chokshi, Stefan Custers, Muhammad Vaseem Shaikh, Petar Miletic, Chitra Venugopal, Kevin R Brown, Rajeev Vibhakar, Jason Moffat, Sheila K Singh.

Glioblastoma (GBM) remains a formidable challenge in clinical settings due to limited treatments available. The surface protein CD133 marks glioblastoma stem cells (GSCs), cells capable of overcoming therapeutic pressures and correlate with more aggressiveness tumor phenotypes. In this study, we employed a CRISPR-Cas9 functional screen to deconvolute CD133 dynamics in tumors. This led us to establish that SOX2 is a key player in controlling the PROM1 gene, which in turn influences how cells react to stress factors, including those induced by chemoradiation treatment. The discoveries in this study shed light on the complex web of mechanisms that control the survival and resistance of GSCs, offering promising new avenues for targeting and potentially overcoming therapy resistance.

DOI: https://doi.org/10.1038/s41598-025-20183-7
Trends Pharmacol Sci. 2025 Oct 11. pii: S0165-6147(25)00225-1. [Epub ahead of print]

Now you serine, now you don't.

Robert B Cameron, Nia G Hammond, Brandon Faubert.

  Cancer cells alter metabolic programs to support uncontrolled growth and proliferation. A new study from Scott and colleagues directly examined tumor metabolism in glioblastoma patients and discovered increased import of the amino acid serine. Excitingly, limiting serine uptake enhanced the effectiveness of chemoradiation in preclinical models of glioblastoma.

Keywords:  glioblastoma; metabolism; stable isotope tracing

DOI:  https://doi.org/10.1016/j.tips.2025.10.001
Front Neurosci. 2025 ;19 1646148

Glioma neuron symbiosis: a hypothesis.

Avital Schurr.

  Glioma cells, just like all cancerous cells, consume substantial amounts of glucose for their energy needs, using glycolysis, an inefficient metabolic pathway (Warburg effect) to produce only two moles of adenosine triphosphate and two moles of lactate for each mole of glucose consumed. By contrast, neurons consume glucose via glycolysis and utilize its end-product lactate as the substrate of the mitochondrial tricarboxylic acid cycle and its coupled oxidative phosphorylation, a process eighteen times more efficient at adenosine triphosphate than glycolysis alone. It hypothesizes here that glioma-produced lactate is the preferred oxidative energy substrate of their surrounding neurons. Consequently, by using lactate, neurons bypass glycolysis, sparing their glucose and making it readily available for the glucose-craving cancer cells. Moreover, glioma cells' ability to secrete glutamate, which excites glutamatergic neurons, could drive the latter to consume even more lactate, sparing more glucose. Such symbiotic exchange, especially at the initial stages of malignancy, assures the budding cancer cells an ample glucose supply ahead of the development of additional vasculature. While this hypothesis focuses on gliomas, it may also apply to other cancer types.

Keywords:  cancer; energy metabolism; glioma; glucose; glycolysis; lactate; neuron; symbiosis

DOI:  https://doi.org/10.3389/fnins.2025.1646148
Oncogene. 2025 Oct 14.

BRD4 inhibition sensitizes glioblastoma to radiotherapy by suppressing super-enhancer-driven COL1A1.

Xichen Fan, Yi Yang, Xuenan Li, Li Yu, Yafei Wang, Ziheng Wang, Shubao Wang, Weichen Duan, Jiajia Chen.

Radiotherapy (RT) combined with chemotherapy is the standard treatment for newly diagnosed glioblastoma (GBM). However, the limited RT efficacy and RT-related cancer resistance have spurred interest in radiosensitizing strategies for GBM. We aimed to explore the synergistic efficacy of the bromodomain-containing protein 4 (BRD4) inhibitor I-BET151 in combination with RT for GBM therapy. We found that BRD4 upregulation after RT was correlated with GBM radiosensitivity. I-BET151 sensitized GBM cells to RT by inhibiting cell proliferation and inducing cell apoptosis, thus prolonging survival in subcutaneous and orthotopic murine GL261 GBM mouse models. In vitro, I-BET151 sensitized GBM cells to RT by suppressing proliferation, inducing apoptosis, and increasing sustainable DNA damage. Mechanistically, integrated H3K27ac ChIP-sequencing and RNA-sequencing analysis identified type I collagen (COL1A1) as a key BRD4-dependent super-enhancer (SE)-driven target post-RT, which was also validated by ChIP‒qPCR. Moreover, RNA interference-mediated COL1A1 silencing reduced proliferation, increased apoptosis, and enhanced RT-induced DNA damage, underscoring its pivotal role in BRD4-mediated radioresistance. In conclusion, BRD4 contributes to extracellular matrix remodeling and radioresistance in a SE-driven COL1A1-dependent manner. Thus, targeting BRD4 is a rational strategy to augment the efficacy of RT for GBM treatment.

DOI: https://doi.org/10.1038/s41388-025-03596-6
Neuro Oncol. 2025 Oct 16. pii: noaf246. [Epub ahead of print]

Phase I/II and Window-of-Opportunity Study of Pamiparib and Metronomic Temozolomide for Recurrent IDH Mutant Gliomas.

David Schiff, Xiaobu Ye, Jing Li, Benjamin M Ellingson, Patrick Y Wen, Tobias Walbert, Jian Campian, L Burt Nabors, Byram H Ozer, Arati Desai, Antonio Omuro, Serena Desideri, Neeraja Danda, Stuart Grossman, Ranjit S Bindra.

   BACKGROUND: Preclinical studies demonstrate activity of PARP inhibitors in IDH mutant gliomas. We investigated safety, tolerability, pharmacokinetics, and efficacy of the PARP inhibitor pamiparib in conjunction with metronomic low-dose temozolomide in patients with recurrent IDH mutant (IDHmt) gliomas in a multicenter Phase I/II/window of opportunity study.
METHODS: Patients received pamiparib in conjunction with daily temozolomide. Following Phase I determination of MTD, we enrolled two patient cohorts (Arm A, multiple prior chemotherapy regimens; Arm B, single prior regimen) in a two-stage design. Exploratory cohorts examined grade 4 IDHmt patients and intratumoral pharmacokinetics of pamiparib. The primary endpoint was objective radiographic response (ORR) by RANO criteria.
RESULTS: 66 subjects were enrolled. We established pamiparib 60 mg twice daily with temozolomide 20 mg daily as the phase II dose. In non-enhancing and enhancing tumor, pamiparib exhibited an unbound tumor/plasma ratio of 0.92 and 0.98 respectively. 0/15 Arm A and 1/24 Arm B patients achieved a centrally confirmed partial response. Median progression-free survival for Arm A was 5.9 months (95% CI, 1.2-14.8 months), and for Arm B 9.7 months (95% CI, 5.7-21.7 months). Grade 3+ anemia and neutropenia affected 24% and 33% of patients respectively. Twenty-two of 66 patients (33.3%) discontinued study treatment for reasons other than tumor progression.
CONCLUSION: Pamiparib appeared to achieve sufficient pharmacologically active concentrations in both enhancing and non-enhancing tumors. While some patients achieved prolonged progression-free survival, combination with temozolomide did not produce a meaningful ORR in IDHmt recurrent gliomas. Cumulative hematologic toxicity was substantial and impacted long-term tolerability.

Keywords:  IDH mutation; PARP inhibitors; clinical trial; glioma; temozolomide

DOI:  https://doi.org/10.1093/neuonc/noaf246
Neuro Oncol. 2025 Oct 14. 27(Supplement_4): iv1-iv66

CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2018-2022.

Mackenzie Price, Christine Ann Pittman Ballard, Julia R Benedetti, Carol Kruchko, Jill S Barnholtz-Sloan, Quinn T Ostrom.

The Central Brain Tumor Registry of the United States (CBTRUS), an aggregation of data from the Centers for Disease Control and Prevention's National Program of Cancer Registries and the National Cancer Institute's Surveillance, Epidemiology and End Results program, is the largest population-based registry focused exclusively on primary brain and other central nervous system (CNS) tumors in the United States (US). As of this report, the CBTRUS database represents the entire US population. This report contains the most up-to-date population-based data on primary brain tumors and supersedes all previous reports in terms of completeness and accuracy. All rates are age-adjusted using the 2000 US standard population and presented per 100,000 population. Between 2018 and 2022, the average annual age-adjusted incidence rate (AAAIR) of all primary malignant and non-malignant brain and other CNS tumors was 26.05 per 100,000 population (malignant AAAIR=6.86 and non-malignant AAAIR=19.19). Incidence was higher in women compared to men (29.67 versus 22.23 per 100,000) and in non-Hispanic Black individuals compared to non-Hispanic White (27.40 versus 26.36 per 100,000), non-Hispanic American Indian/Alaska Native (24.38 per 100,000), non-Hispanic Asian or Pacific Islander (20.42 per 100,000), and Hispanic individuals of all races (24.69 per 100,000). Gliomas accounted for 22.2% of all tumors. The most commonly occurring malignant brain and other CNS histopathology was glioblastoma (13.7% of all tumors and 52.2% of all malignant tumors), and the most common non-malignant histopathology was meningioma (42.6% of all tumors [includes malignant meningioma] and 57.4% of all non-malignant tumors). Glioblastoma was more common in men, and meningioma was more common in women. In children and adolescents (ages 0-19 years), the incidence rate of all primary brain and other CNS tumors was 5.99 per 100,000 population. Overall, there were 88,186 total deaths attributed to  malignant brain and other CNS tumors between 2018 and 2022, representing an average of 17,637 deaths per year and an average annual mortality rate of 4.41 per 100,000 population. The five-year relative survival rate following diagnosis of a malignant brain or other CNS tumor was 34.8%, while it was 91.7% for a non-malignant brain or other CNS tumor.

DOI: https://doi.org/10.1093/neuonc/noaf194