bims-malgli 2026-04-05 papers

bims-malgli

Biomed News

on Biology of malignant gliomas

Issue of 2026–04–05
nine papers selected by
Oltea Sampetrean, Keio University

PTBP1 knockdown reprograms glioma stem cells into neuronal-like cells and suppresses tumorigenesis via the DUSP5-ERK1/2 signaling pathway.
Exploring the immune environment of glioblastoma in humanized mouse models.
Expanding the molecular grading criteria in IDH-mutant astrocytoma.
Effects of short- and long-term mutant IDH1 inhibition on radiosensitivity across genetically diverse patient-derived IDH1-mutant glioma cells.
Attract to kill: Exploring the potential of motility trapping as a novel treatment strategy for high-grade gliomas.
Highlights in IO: next-generation CAR-T therapy for glioblastoma.
Adoptive cellular therapy prevents reconstitution of myeloid-derived suppressor cells in the glioma tumor microenvironment.
Objective characterization of displacement of the frontal aslant tract in low-grade glioma: a quantitative tractography study.
Microglia-glioblastoma crosstalk mediates glioblastoma invasion at the far infiltration zone.

Neuro Oncol. 2026 Mar 28. pii: noag068. [Epub ahead of print]

PTBP1 knockdown reprograms glioma stem cells into neuronal-like cells and suppresses tumorigenesis via the DUSP5-ERK1/2 signaling pathway.

Cunyu Li, Manyu Chen, Songyi Guo, Yuhao Ma, Suli Zhang, Guanwei Li, Jianqi Wu, Tianqi Liu, Yueyi Jin, Xing Liu, Hu Zhao, Hongmei Liu, Sijin Wu, Hangjin Jiang, Wen Cheng, Anhua Wu, Shuang Hao.

   BACKGROUND: Glioblastoma (GBM), the most prevalent and aggressive primary brain tumor in adults, has a median survival of merely 14 months. Current therapeutic approaches, including maximal safe resection, radiotherapy, and temozolomide-based chemotherapy, have limited efficacy owing to resistance and the high rate of recurrence.
METHODS: We analyzed H&E-stained specimens from 65 patients with glioma using deep learning-based morphological classification and analyzed a mouse model through tissue clearing and 3D imaging. Integrated transcriptomic and single-cell RNA-seq analyses identified PTBP1 as a morphology regulator. We validated the function of PTBP1 through lentiviral knockdown in vitro and in orthotopic models and performed structure-based drug screening against PTBP1 with experimental validation.
RESULTS: We detected a clinically significant association between glioma cell morphology and patient survival times. Mechanistically, PTBP1, an RNA-binding protein abundantly expressed in glioma cells, regulated dual-specificity phosphatase 5 (DUSP5) expression post-transcriptionally and modulate ERK1/2 phosphorylation dynamics, thus reducing glioma stem cell proliferation and enhancing differentiation into neuronal-like cells to suppress tumor growth. Importantly, we developed a nanotherapeutic strategy using A2-PLGA/venetoclax; this strategy repurposes venetoclax, a known clinical drug for leukemia, as a PTBP1-targeting agent that effectively suppresses glioma progression in mouse models.
CONCLUSION: Our findings establish a novel PTBP1/DUSP5/ERK1/2 axis governing glioma stem cell proliferation and differentiation and identify the A2-PLGA/venetoclax nanoparticle as a mechanistically justified therapeutic candidate for glioblastoma.

Keywords:  A2-PLGA/venetoclax; Glioma stem cells; PTBP1; cell differentiation; neuronal-like cells

DOI:  https://doi.org/10.1093/neuonc/noag068
Neuro Oncol. 2026 Mar 30. pii: noag073. [Epub ahead of print]

Exploring the immune environment of glioblastoma in humanized mouse models.

Jun Takei, Ken Furudate, Yoshiko Nagaoka-Kamata, Opeyemi Iwaloye, Naoki Hama, Chloe E Jepson, Madison T Blucas, Lewis Barr, Kiyotaka Saito, Robert S Welner, Erwin G Van Meir, Masakazu Kamata, Satoru Osuka.

   BACKGROUND: Glioblastoma (GBM) is the deadliest primary brain tumor in adults, where current therapies fail to extend survival meaningfully. Available animal GBM tumor models, especially therapy-resistant and recurrent models with human tumor and human immune cell interactions, are limited, impeding innovative treatment research. To address this critical obstacle, we established a unique GBM mouse model using patient-derived xenografts (PDXs) in humanized mice.
METHODS: We selected two immunodeficient mouse models that express key human cytokines required for the proper reconstitution of myeloid lineage cells. After undergoing myeloablation, mice received CD34+ hematopoietic stem progenitor cells derived from human umbilical cord blood for humanization. Upon confirming the reconstitution of human blood cells, mice were xenografted with radiation-resistant PDXs. Tumor profiles and immune cell infiltration were analyzed via spectral flow cytometry, immunohistochemistry, and single-cell RNA sequencing (scRNA-seq). The results were benchmarked against scRNA-seq data from patients with recurrent human GBM.
RESULTS: A diverse range of human immune cells, including T cells, natural killer cells, and myeloid lineage cells, infiltrated PDX tumors in humanized mice. Notably, gene expression profiles in these immune cells resembled those of recurrent human GBM. Unlike conventional xenograft models, this model highlighted enhanced tumor diversity, particularly a high fraction of neural progenitor-like cells.
CONCLUSIONS: Our humanized GBM mouse model exhibited an immune cell signature similar to that of human recurrent GBM. This model is a valuable resource for analyzing the tumor immune landscape and assessing new therapies, particularly immunotherapies.

Keywords:  and tumor heterogeneity; glioblastoma; humanized mice; immune microenvironment; single-cell RNA sequencing

DOI:  https://doi.org/10.1093/neuonc/noag073
Neuro Oncol. 2026 Mar 28. pii: noag069. [Epub ahead of print]

Expanding the molecular grading criteria in IDH-mutant astrocytoma.

Michael Christian Virata, Jorge Samanamud, Cheyanne C Slocum, Shrishtee Kandoi, Phuong Nguyen, Milan R Savani, Diana D Shi, Sachein Sharma, Satomi Hiya, Carolina Maldonado-Díaz, Kevin Clare, Raquel T Yokoda, Meenakshi Vij, Ema Mir, Yurika Nishikawa, Melissa Umphlett, Raymund L Yong, Joshua B Bederson, Thenzing J Silva-Hurtado, Steven Brem, Dolores Hambardzumyan, Matija Snuderl, Mariano S Viapiano, Kalil G Abdullah, Samuel K McBrayer, Kimmo J Hatanpaa, Jamie M Walker, Nadejda M Tsankova, Timothy E Richardson.

   BACKGROUND: IDH-mutant astrocytomas are classified as WHO grade 4 in the presence of conventional high-grade histologic features and/or homozygous CDKN2A/B deletion in the 5th edition of the WHO Classification of Central Nervous System Tumour guidelines. However, work over the past decade has indicated a number of other molecular alterations that warrant consideration as potential prognostic markers.
METHODS: We used univariate Kaplan-Meier and multivariate Cox proportional hazards regression analysis to evaluate the prognostic effects of homozygous CDKN2A/B deletion, CDK4 amplification, CCND2 amplification, PDGFRA amplification/mutation, PIK3R1 mutation, PIK3CA mutation, MYCN amplification, EGFR amplification/mutation, TERT promoter mutation, and grade 4 histologic features in two independent cohorts of WHO grade 2-4 IDH-mutant astrocytoma (n = 840 and n = 367).
RESULTS: The presence of CDK4 amplification, CCND2 amplification, PDGFRA alteration, PIK3R1 mutation, MYCN amplification, and EGFR alteration were each associated with reduced overall survival compared to WHO grade 2/3 astrocytomas without these molecular features. 17.7% (148/837) of otherwise grade 2/3 astrocytomas had one or more of these molecular criteria, with resulting intermediate clinical outcome in terms of overall survival (median survival of 67.3-82.0 months) compared to grade 2/3 astrocytomas without these molecular features (median survival of 135.0-140.7 months) and grade 4 astrocytomas (median survival of 35.3-45.0 months).
CONCLUSIONS: The presence of CDK4, CCND2, PDGFRA, PIK3R1, MYCN, and EGFR alterations result in an intermediate patient survival in IDH-mutant astrocytoma. Adding these molecular alterations should be considered in future diagnostic classification systems to improve stratification of high-risk patients.

Keywords:  Astrocytoma; diffuse glioma; genetic heterogeneity; glioblastoma; oligodendroglioma

DOI:  https://doi.org/10.1093/neuonc/noag069
Neurooncol Adv. 2026 Jan-Dec;8(1):8(1): vdag057

Effects of short- and long-term mutant IDH1 inhibition on radiosensitivity across genetically diverse patient-derived IDH1-mutant glioma cells.

Yosuke Kitagawa, Logan D Muzyka, Ami Kobayashi, Ethan Wetzel, Ali Nasser, Julie J Miller, Hiroaki Wakimoto, Daniel P Cahill.

   Background: IDH mutant gliomas produce the oncometabolite 2-hydroxyglutarate (2-HG), driving tumorigenesis through metabolic dysregulation and epigenetic alterations. IDH inhibitors (IDHi) reduce 2-HG and are clinically approved for treating IDH mutant gliomas. However, the observed impact of IDHi therapy on tumor response to ionizing radiation (IR) has been variable across murine models and engineered cell lines.
Methods: We investigated the effects of short-term (5 days) and long-term (≥5 weeks) exposure to the IDH1 inhibitor AGI-5198 on radiation-induced cytotoxicity. Patient-derived glioma neurosphere lines (MGG119, TS603S2, BT142, and MGG152) were studied, with IDH1-mutant fibrosarcoma HT1080 and an inducible IDH1-R132H glioma line (MGG18 Tet±). Intracellular 2-HG, cell viability, and clonogenic survival were measured following IR.
Results: AGI-5198 potently reduced intracellular 2-HG across all IDH1-mutant lines after short-term treatment, with suppression maintained during prolonged exposure but rapidly reversed upon withdrawal. Long-term AGI exposure produced cell viability responses to both standard- and high-dose IR comparable to short-term treatment in HT1080, TS603S2, BT142, MGG152, and MGG18 Tet±. Across endogenous IDH-mutant models, neither short- nor long-term IDH inhibition induced radioresistance. MGG119, harboring IDH1-R132H and MET alterations, showed intrinsic radioresistance unaffected by IDHi. In contrast, MGG152, harboring IDH1-R132H and BRCA2 mutations, exhibited modest radiosensitization with IDHi.
Conclusions: Prolonged AGI-5198 exposure does not reduce IR sensitivity in IDH mutant glioma cells. Effects were comparable to short-term treatment, while radiation responses varied by genetic context. No deleterious interaction between IDHi and IR was observed in endogenous IDH-mutant cells except for MGG18 Tet+ supporting integration of IDHi with radiotherapy in IDH mutant gliomas.

Keywords:  2-hydroxyglutarate; IDH inhibitor; cytotoxicity; glioma; radiation therapy

DOI:  https://doi.org/10.1093/noajnl/vdag057
Neuro Oncol. 2026 Mar 28. pii: noag067. [Epub ahead of print]

Attract to kill: Exploring the potential of motility trapping as a novel treatment strategy for high-grade gliomas.

Anne-Sophie Bamelis, Dennis Serge Metselaar, Mariska Sie, Thibault Lootens, Leen Willems, Robrecht Raedt, Jelle Vandersteene.

  High-grade gliomas (HGG) are notoriously hard to treat due to surgical limitations and resistance to systemic therapies, resulting in a dire prognosis. Tumor cell motility is a major contributor to treatment failure but simultaneously offers a therapeutic opportunity, utilizing a novel approach called "motility trapping". Motility trapping leverages chemotactic signals to redirect tumor cells to a location where local therapies can target them more effectively. This concept can be applied inward, drawing disseminating tumor cells back to the primary tumor, or outward, guiding them toward a more therapy-accessible location. While preclinical research demonstrates that motility trapping can influence tumor migration, clinical translation remains unestablished. To advance clinical applicability, four essential components must be considered: effective migratory stimuli, susceptible tumor cells, suitable delivery systems, and the influence of the tumor microenvironment. For each element, we review current knowledge and propose future directions to develop this innovative approach. In conclusion, redirecting HGG migration through motility trapping offers a transformative strategy that warrants further preclinical and translational investigation. It holds promise to synergize with a plethora of therapeutic strategies that are currently ineffective in brain tumors, and should be considered in the design of future therapies.

Keywords:  chemotaxis; high-grade glioma; local therapy; motility trapping; tumor cell motility

DOI:  https://doi.org/10.1093/neuonc/noag067
J Immunother Cancer. 2026 Apr 01. pii: e014670. [Epub ahead of print]14(4):

Highlights in IO: next-generation CAR-T therapy for glioblastoma.

Junya Yamaguchi, Hideho Okada.

  Over the past few years, outcomes and findings from several phase 1 clinical trials evaluating chimeric antigen receptor (CAR)-T cell therapies for glioblastoma (GBM) have been reported. For CAR-T cell therapy to succeed in GBM, several challenges must be overcome, including the immunosuppressive microenvironment (immunosuppressive cells, hypoxia, and metabolic constraints), antigen heterogeneity, and the anatomically isolated environment. To address these challenges, next-generation CAR-T cells-those engineered with additional functionalities-have been developed, and phase 1 clinical trials evaluating these next-generation CAR-T therapies for GBM have now been initiated. The development of CAR-T therapy for GBM has entered a new chapter. To date, the antitumor efficacy of CAR-T therapies still needs to be improved, and the high frequency of neurotoxicity remains a major issue that needs to be addressed; however, there is a growing anticipation that next-generation CAR-T therapies may provide clinical benefit to patients.

Keywords:  Adoptive cell therapy - ACT; Central Nervous System Cancer; Chimeric antigen receptor - CAR; Immunotherapy

DOI:  https://doi.org/10.1136/jitc-2025-014670
Neurooncol Adv. 2026 Jan-Dec;8(1):8(1): vdag054

Adoptive cellular therapy prevents reconstitution of myeloid-derived suppressor cells in the glioma tumor microenvironment.

John W Figg, Caitland Love, Sofia Stansbury, Dan Jin, Connor Francis, Bayli DiVita Dean, Alexandra Reid, Mia Engelbart, Illeana West, Laura Falceto Font, Diana Feier, Ghaidaa Ebrahim, Rachael Bessey, David Hilferty, Oleg Yegorov, Changling Yang, Kaytora Long-James, Duane A Mitchell, Catherine T Flores.

   Background: Glioblastoma (GBM) is an aggressive brain cancer infiltrated by immunosuppressive myeloid-derived suppressor cells (MDSCs) and confers poor prognosis. To address this, our group developed an adoptive cellular therapy platform specifically for primary central nervous system (CNS) malignancies that yielded significant survival benefits against multiple brain cancer models. Preclinically, this platform establishes proof-of-concept for lymphodepletion achieved through host conditioning with total body irradiation (TBI). While host conditioning is thought to remove immunosuppressive elements, the aim of this study was to determine how immune recovery is affected by adoptive cellular therapy.
Methods: The adoptive cellular therapy platform includes myeloablative TBI, hematopoietic stem cell rescue, tumor-specific T cells, and dendritic cell vaccines. KR158B glioma-bearing mice were treated with adoptive cellular therapy and secondary lymphoid organs were evaluated using flow cytometry, spatial genomics, and multiplex protein analysis. Single-cell transcriptomics and trans-well migration assay evaluated the role of CCL12 on MDSC migration.
Results: We show that adoptive cellular therapy allows for reconstitution of MDSC and tumor-associated macrophages in secondary lymphoid organs but prevents their accumulation in the tumor microenvironment (TME). This allows for the increased engraftment and activation of T cells within the TME. Next, we show that adoptive cellular therapy decreases CCL12 in the TME and neutralization of TAM-derived CCL12 in vitro inhibits MDSC migration in glioma.
Conclusion: These findings suggest a previously unrecognized association between both loss of intratumoral immunosuppressive elements after immunotherapy and TAM-derived CCL12, a chemokine that promotes MDSC migration. Future in vivo studies will evaluate the causal role of CCL12 on MDSC recruitment in glioma.

Keywords:  CCL12; MDSC; adoptive immunotherapy; glioblastoma; migration

DOI:  https://doi.org/10.1093/noajnl/vdag054
Neuroradiology. 2026 Apr 01.

Objective characterization of displacement of the frontal aslant tract in low-grade glioma: a quantitative tractography study.

A L Mahmoodi, L Smolders, M J F Landers, G J M Rutten, H B Brouwers.



Keywords:  Dice similarity coefficient; Glioma; Hausdorff distance; Spatial metrics; Tractography; White matter tract alteration pattern

DOI:  https://doi.org/10.1007/s00234-026-03968-z
Immunity. 2026 Mar 31. pii: S1074-7613(26)00121-4. [Epub ahead of print]

Microglia-glioblastoma crosstalk mediates glioblastoma invasion at the far infiltration zone.

Felix C Nebeling, Falko Fuhrmann, Manuel Mittag, Fabrizio Musacchio, Henrike Antony, Nala Gockel, Lea L Friker, Sonia Leonardelli, Severin Filser, Deli A, Miriam Stork, Daniele Bano, Torsten Pietsch, Frank A Giordano, Qihui Zhou, Simona Parrinello, Michael Hölzel, Ulrich Herrlinger, Paolo Salomoni, Martin Fuhrmann.

  Glioblastoma (GB) cells infiltrate the brain parenchyma and colonize distant regions, driving recurrence and therapy resistance. Here, we examined dynamic microglial responses to infiltrating tumor cells during GB progression. Three-photon imaging in an autochthonous, immunocompetent GB mouse model enabled visualization of microglia-GB interactions at the far infiltration zone (FIZ) in the corpus callosum (CC). GB infiltration speed varied by anatomical location and tumor microtube (TM) number. Microglia increased surveillance in sparsely infiltrated areas but reduced it with higher GB density, revealing a biphasic response. Directional migration toward GB cells was restricted to microglial subsets within a defined spatial range, indicating heterogeneous reactivity. CX3CR1 deficiency enhanced microglial reactivity while limiting GB cell migration. Microglia depletion with the CSF1R inhibitor PLX5622 reduced GB cell migration and constrained TM plasticity. Thus, microglia respond to GB cell infiltration in a stage-dependent manner and critically modulate dissemination at the FIZ.

Keywords:  CSF1R inhibition; CX3CR1-deficiency; Corpus callosum; autochthonous mouse model; diffuse infiltration; glioblastoma; microglia; migration; motility; three-photon microscopy; tumor microtubes

DOI:  https://doi.org/10.1016/j.immuni.2026.03.010