bims-malgli 2026-01-25 papers

bims-malgli

Biomed News

on Biology of malignant gliomas

Issue of 2026–01–25
eight papers selected by
Oltea Sampetrean, Keio University

ETC-501 is a Brain Penetrant MNK Kinase Inhibitor that Potentiates TMZ-Induced Senescence and Sensitizes Glioblastoma Cells to Senolytic Therapy.
Reactive oligodendrocytes promote glioblastoma progression through CCL5/CCR5-mediated glioma stem cell maintenance.
Intermittent fasting inhibits Tp53-driven glioma through gut microbiota-mediated methionine-m6A regulation.
IGF2 supports glioblastoma growth and immune evasion through a combination of tumor cell-intrinsic and -extrinsic mechanisms.
S1PR3 mediates glial stimulated tumor invasion in response to interstitial fluid flow.
Single-Cell Multiomic Profiling Uncovers Radiation Dosage-Sensitive, Cluster-Specific Regulatory Dynamics in Glioblastoma.
Transsynaptic tracing techniques to interrogate neuronal connectivity of glioblastomas.
Beyond Cell Cycle Control: CDKN2A Loss Orchestrates NAD + Metabolic Plasticity and NAMPT Inhibitor Sensitivity in Glioblastoma.

Cancer Res. 2026 Jan 22.

ETC-501 is a Brain Penetrant MNK Kinase Inhibitor that Potentiates TMZ-Induced Senescence and Sensitizes Glioblastoma Cells to Senolytic Therapy.

Giselle Sek Suan Nah, Yuk Kien Chong, Fatin Nasha Sulaimi, Kian Leong Lee, See Wee Lim, Qing You Pang, Mengge Yu, Zhen Wei Neo, Jabed Iqbal, Kassoum Nacro, Jeffrey Hill, Alex Matter, Henry Yang, Beng Ti Ang, Carol Tang, S Tiong Ong.

Glioblastoma (GBM) is the deadliest primary brain tumor in adults, with a median survival of only 15 months and fewer than 10% of patients surviving beyond 5 years. Despite aggressive multimodal therapies, including surgical resection, radiation, and temozolomide (TMZ) chemotherapy, recurrence is almost inevitable. The MNK-eIF4E axis plays a significant role in cancer cell survival, and MNK1 and MNK2 are upregulated in gliomas. In this study, we discovered that elevated MNK1/2 expression correlates with poor prognosis and aggressive GBM phenotypes. Development of ETC-501, a selective brain-penetrant MNK kinase inhibitor, enabled modulation of key oncogenic pathways, including MYC signaling, DNA replication, cell cycle regulation, and inflammation. ETC-501 effectively inhibited GBM proliferation, impaired DNA damage repair, delayed cell cycle progression, and suppressed ribosome biogenesis. Notably, in combination with TMZ, ETC-501 not only enhanced senescence but also attenuated the senescence-associated secretory phenotype in GBM cells. The augmented senescence increased the vulnerability of GBM cells to the senolytic agent navitoclax, facilitating targeted elimination of residual senescent cells. These findings underscore the therapeutic potential of MNK inhibition in GBM, offering a promising strategy to advance GBM treatment paradigms and improve patient outcomes.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-4388
Neuron. 2026 Jan 21. pii: S0896-6273(25)00939-0. [Epub ahead of print]114(2): 237-249.e10

Reactive oligodendrocytes promote glioblastoma progression through CCL5/CCR5-mediated glioma stem cell maintenance.

Nicholas Mikolajewicz, Kui Zhai, Anish Puri, Petar Miletic, Nazanin Tatari, Jiarun Wei, Neil Savage, Zhi Huang, Qian Huang, Seon Yong Lee, Mahta Jan-Ahmadnejad, Roseanne Nguyen, David Chen, Tiegan Korman, Daniel Mobilio, Maxwell Topley, Jack Qinyu Lu, Matthew R Voisin, Zsolt Zador, Shawn C Chafe, Chitra Venugopal, Kevin R Brown, Gelareh Zadeh, Hong Han, Julien Muffat, Shideng Bao, Sheila K Singh, Jason Moffat.

  Glioblastoma (GBM) evolves within a microenvironment abundant in oligodendrocyte-lineage (OL) cells. In this study, we utilized single-cell and spatial transcriptomics from primary and recurrent GBM tumors, immunohistochemistry, cytokine profiling, and migration assays to show that GBM cells recruit OLs to the tumor border via fractalkine (i.e., CX3CL1/CX3CR1) signaling. A pan-disease human OL meta-atlas and syngeneic mouse models reveal an interferon (IFN)-induced reactive OL state, akin to those seen in demyelinating inflammatory and traumatic injury, which is enriched in central nervous system malignancies. These reactive OLs secrete pro-tumorigenic cytokines, notably C-C motif chemokine ligand 5 (CCL5), that promote GBM tumor cell growth through C-C chemokine receptor type 5 (CCR5) signaling. CCR5 is preferentially expressed in glioma stem-like cells (GSCs) and upregulated at recurrence. Targeting CCR5 with genetic knockdown or the approved drug maraviroc impairs GSC stemness and prolongs survival in GBM models. Our work highlights the functional interplay between OLs and GBM cells and positions the CCL5/CCR5 axis as a druggable target in GBM.

Keywords:  CCL5; CCR5; CX3CL1; CX3CR1; glioblastoma; glioma stem cells; maraviroc; oligodendrocyte progenitor cells; oligodendrocytes; single-cell transcriptomics

DOI:  https://doi.org/10.1016/j.neuron.2025.12.012
Nat Commun. 2026 Jan 20.

Intermittent fasting inhibits Tp53-driven glioma through gut microbiota-mediated methionine-m6A regulation.

Yao Lin, ShihJung Li, Xinyue Xu, Xiaopeng Hu, Yueqi Li, Shuaiyi Liang, Jun Meng, Honglei Li, Zheng Li, Dandan Xiong, Hubin Chen, Jingzhen Lai, Yi Bao, Ziyi Liu, Jiemei Chu, Xuena Chen, Xianning Zhang, Xinli Liu, Shiou Yih Lee, Sanqi An.

Intermittent fasting (IF) has emerged as a potential cancer treatment modality, although its tumor-suppressive effects are limited. Glioblastoma (GBM) can be classified into CDKN2A subtype and TP53 subtype. Here, we discover that the efficacy of IF is correlated with tumor subtypes of GBM. IF significantly inhibite GBM progression in mice with the Tp53 GBM model, whereas its inhibitory effect is not significant in the Cdkn2a GBM model. Multi-omics sequencing is performed in the IF-responsive Tp53 GBM mouse model, delineating a comprehensive molecular profiling of IF that including the spatial transcriptome, spatial metabolome, single-cell transcriptome, single-cell RNA methylation, metabolome, and microbiome. Through systematic biological analysis and rescue experiments conducted in IF-responsive Tp53 GBM mice model, we demonstrate that the efficacy of IF is primarily mediated by alterations in the gut microbiota, which subsequently modulate the production of the microbial metabolite methionine sulfoxide. Methionine sulfoxide, by regulating m6A modification, inhibits the TGF-β signaling pathway, resulting in suppressing GBM progression. This study proposes a genotype-based hypothesis for the therapeutic effects of IF on tumors, and elucidates the potential RNA modification-related molecular mechanisms underlying the effective suppression of GBM by IF.

DOI: https://doi.org/10.1038/s41467-026-68512-2
Neurooncol Adv. 2026 Jan-Dec;8(1):8(1): vdaf226

IGF2 supports glioblastoma growth and immune evasion through a combination of tumor cell-intrinsic and -extrinsic mechanisms.

Kyle M Heemskerk, Samir Assaf, Xiaoguang Hao, Shannon Snelling, Mathieu Meode, Rozina Hassam, Orsolya Cseh, Smriti Kala, James Pemberton, Jennifer A Chan, John Gregory Cairncross, Peter Forsyth, Voon Wee Yong, Reza Mirzaei, Samuel Weiss, Franz J Zemp, Hema Artee Luchman.

   Abstract: BackgroundGIntratumoral and intertumoral heterogeneity combined with immunosuppressive tumor microenvironments (TME) contribute to the poor outcomes associated with glioblastoma (GBM). Well-characterized immunocompetent models that recapitulate human GBM features are urgently needed to identify targets in the TME and develop novel therapeutics. Here, we used multiomic approaches to characterize syngeneic mouse brain tumor stem cell lines in vitro and in orthotopically engrafted tumors.
Methods: Whole-genome sequencing, transcriptomics, ATAC-sequencing, and imaging mass cytometry were used to characterize syngeneic brain tumor stem cell lines derived from Trp53+/-/Nf1+/- C57Bl6 mice. Mouse and human bulk, single-cell, and spatial sequencing datasets were analyzed for validation. CRISPR/Cas9 and shRNA were used for gene knockdowns. Tumor growth was investigated using orthotopic engraftment in syngeneic C57Bl6 mice.
Results: One of the syngeneic lines, mBT0309, generated tumors with histopathological characteristics of GBM. mBT0309 displayed amplification and high expression of Igf2. Copy number gains at the IGF2 locus were observed in human GBM tumors and stem cell lines. Furthermore, we determined that high IGF2 RNA expression is associated with poor survival in GBM patients. Imaging mass cytometry on mBT0309 tumors showed early infiltration of monocyte-derived macrophages, vascularization, and cell states characteristic of human GBM. Genetic targeting of Igf2 decreased in vitro cell growth, improved survival of engrafted mice, and decreased the percentage of Arginase-1+ macrophages in mBT0309 tumors.
Conclusions: mBT0309 is a valuable syngeneic model for studying immunosuppression and therapeutic resistance in GBM. IGF2 offers promise as a valuable therapeutic target to combat tumor growth and immunosuppression in GBM patients.

Keywords:  brain tumor stem cells; glioblastoma; insulin-like growth factor 2; multiomics; syngeneic model

DOI:  https://doi.org/10.1093/noajnl/vdaf226
bioRxiv. 2025 Dec 03. pii: 2025.12.01.690522. [Epub ahead of print]

S1PR3 mediates glial stimulated tumor invasion in response to interstitial fluid flow.

R Chase Cornelison, Samantha Howerton, Kinsley M Tate, Caleb A Stine, Alexis Petrosky, Kathryn M Kingsmore, Sharon K Michelhaugh, Jessica J Cunningham, Katie Degen, Austin Hoggarth, Cora Carman-Esparza, Peng Jin, Maosen Wang, Caroline O'Brien, Aizhen Xiao, Benjamin W Purow, James W Mandell, Ian F Kimbrough, Mark R Witcher, Jennifer M Munson.

Cellular invasion is a primary challenge to complete resection and treatment of glioblastoma, the most aggressive and deadly primary brain tumor. The brain tumor microenvironment actively stimulates glioma invasion through a multitude of cellular, chemical, and biophysical cues. We and others have shown elevated interstitial fluid flow at the tumor border is one such biophysical cue that directly stimulates invasion through tumor-intrinsic signaling and, in other tumor types, priming of cancer-associated stromal cells. It is currently unclear if interstitial flow similarly primes neuroglial cells to promote glioma cell dissemination and can be targeted for therapeutic purposes. Here, we show elevated interstitial flow upregulates expression of sphingosine-1-phosphate receptor 3 (S1PR3) in glial astrocytes and microglia, which drives glioma cell invasion via chemotaxis. Flow-induced expression of glial S1PR3 is tumor-independent and displays a biphasic relationship to fluid shear stress magnitude in vitro and flow rate in vivo . Inhibition of glial S1PR3 in a tissue engineered culture model and orthotopic mouse model abrogates flow-stimulated invasion, demonstrating a tumor-extrinsic approach to limiting glioblastoma progression. Given prior evidence of a pro-inflammatory role for glial S1PR3, identification of S1PR3 as a disease-agnostic marker of flow-stimulated glia may also have therapeutic implications across myriad neuropathologies.

DOI: https://doi.org/10.64898/2025.12.01.690522
bioRxiv. 2025 Dec 03. pii: 2025.12.01.691699. [Epub ahead of print]

Single-Cell Multiomic Profiling Uncovers Radiation Dosage-Sensitive, Cluster-Specific Regulatory Dynamics in Glioblastoma.

Khoi Huynh, Sara Nalina Barcik Weissman, Cheol Park, Maria L G Quiloan, Blake Sun Chang, Eric Chang, Kelly Street, David Tran, Aram S Modrek.

Glioblastoma (GBM) is an aggressive brain tumor that inevitably recurs after chemoradiotherapy, resulting in poor patient outcomes. Given GBM's cellular heterogeneity, we hypothesized that radiation induces sub-population specific alterations to survive and adapt to radiation stress. We performed integrated single-cell RNA-seq and ATAC-seq analyses in Glioma Stem-Like Cultures three hours after they were exposed to clinically relevant radiation doses. Radiation reshaped the cellular landscape, altering both cell type composition and GBM subtype distribution. Cluster-specific and shared transcriptional programs were induced in a dose-dependent manner, with differentially expressed genes enriching distinct biological pathways. Chromatin accessibility analyses revealed parallel cluster-specific remodeling, with both opening and closing of regulatory elements linked to functional pathway shifts. Notably, 2 Gy and 6 Gy exposures elicited conserved transcriptional profiles in RNA clusters across different radiation doses. Together, these results highlight immediate radiation-induced transcriptional and chromatin remodeling programs in GBM at single-cell resolution and identify conserved cluster-specific adaptations that may underlie therapeutic resistance.

DOI: https://doi.org/10.64898/2025.12.01.691699
Nat Protoc. 2026 Jan 21.

Transsynaptic tracing techniques to interrogate neuronal connectivity of glioblastomas.

Yusha Sun, Xin Wang, Zhijian Zhang, Guo-Li Ming, Hongjun Song.

Glioblastomas (GBMs) functionally integrate into diverse neuronal circuits within the central nervous system, which can promote tumor progression and affect neurons via neuron-to-glioma synapses. It remains challenging to identify and manipulate tumor-innervating neurons, which may remain localized or widely distributed throughout the brain. Building on GBM organoids (GBOs) derived from patient-resected surgical tissue, we present here detailed procedures for assessing interactions between tumors and neurons. We first discuss retrograde trans-monosynaptic tracing approaches to study the neuron-tumor connectome by using a rabies viral system in ex vivo human tissue and in xenogenic animal models. As a complementary approach, we then describe the use of anterograde transsynaptic tracing using herpes simplex virus in vivo and ex vivo to assess brain region-specific connectivity in GBMs. In addition, to facilitate the adaptability of these tracing methodologies in diverse systems, we provide procedures for the viral transduction into GBOs, the generation of assembloids comprising GBOs and human induced pluripotent stem cell-derived cortical organoids and the establishment of air-liquid interface cultures from surgical human brain tissue. Together, these techniques permit the flexible characterization and manipulation of tumor-neural circuits and can be easily adapted to other cancers with nervous system involvement. After the generation of GBOs and/or cortical organoids, transsynaptic tracing requires 12-35 d to complete ex vivo or in vivo. The procedure is suitable for users with expertise in human cell and organoid culture, viral production and transduction, rodent surgery and microscopy.

DOI: https://doi.org/10.1038/s41596-025-01287-w
bioRxiv. 2025 Dec 04. pii: 2025.12.02.691903. [Epub ahead of print]

Beyond Cell Cycle Control: CDKN2A Loss Orchestrates NAD + Metabolic Plasticity and NAMPT Inhibitor Sensitivity in Glioblastoma.

Swati Dubey, Guanqiao Yu, Ryana Aboul-Hosn, Christopher Tse, David A Nathanson, Albert Lai, Keith Vossel, Fausto J Rodriguez.

While CDKN2A loss is classically associated with cell cycle deregulation through the p16-Cdk4-Rb axis, our findings suggest an additional layer of metabolic vulnerability arising from altered NAD homeostasis in CDKN2A -deleted glioblastoma, revealing a previously unrecognized metabolic-genetic interface for rationally revisiting NAD + targeting strategies, moving beyond the broad inhibition approaches.

DOI: https://doi.org/10.64898/2025.12.02.691903