bims-malgli 2025-06-01 papers

bims-malgli

Biomed News

on Biology of malignant gliomas

Issue of 2025–06–01
nine papers selected by
Oltea Sampetrean, Keio University

Metabolic flux analysis of glioblastoma neural stem cells reveals distinctive metabolic phenotypes in ketogenic conditions.
Elevated nonhomologous end-joining by AATF enables efficient DNA damage repair and therapeutic resistance in glioblastoma.
Transient mRNA CAR T cells targeting GD2 provide dose-adjusted efficacy against diffuse midline glioma and high grade glioma models.
Polyamine acetylation mediates crosstalk between cancer cells and myeloid cells to promote mesenchymal/plurimetabolic states in glioblastoma.
The Basis for Targeting the Tumor Macrophage Compartment in Glioblastoma Immunotherapy.
Expanding the Immunotherapeutic Toolbox in Glioblastoma: A Safe and Feasible Strategy at the Point of Surgery.
Development of an Anti-CD99 Antibody Enables Targeting of Diffuse Midline Glioma.
Post-translational modifications in DNA damage repair: mechanisms underlying temozolomide resistance in glioblastoma.
Interactions between cancer cells and immune cells drive transitions to mesenchymal-like states in glioblastoma.

Sci Rep. 2025 May 28. 15(1): 18736

Metabolic flux analysis of glioblastoma neural stem cells reveals distinctive metabolic phenotypes in ketogenic conditions.

Anna Rushin, Aleezeh Shaikh, Callie Hardin, Loic P Deleyrolle, Matthew E Merritt.

  Glioblastomas (GBM) are the most prevalent primary brain tumors, affecting 5 in every 100,000 people. GBMs optimize proliferation through adaptive cellular metabolism, frequently exploiting the Warburg effect by increasing aerobic glycolysis and glucose utilization to facilitate rapid cell growth. This disproportionate reliance on glucose has driven interest in using the ketogenic diet (KD) as a treatment for GBM. In this study, we explored metabolic flux in three primary human GBM cell samples using a media simulating a KD. Flux analysis using a detailed metabolic modeling approach revealed three unique metabolic phenotypes in the patient GBMs that correlated with cell viability. Notably, these phenotypes are apparent in the flux modeling, but were not evidenced by changes in the metabolite pool sizes. This variability in metabolic flux may underlie the inconsistent results observed in preclinical and clinical studies using the KD as a treatment paradigm.

Keywords:  Cancer biology; Glioblastoma; Isotopic analysis; Ketogenesis; Metabolism

DOI:  https://doi.org/10.1038/s41598-025-02124-6
Nat Commun. 2025 May 28. 16(1): 4941

Elevated nonhomologous end-joining by AATF enables efficient DNA damage repair and therapeutic resistance in glioblastoma.

Lanjuan Mi, Yan Cai, Ji Qi, Lishu Chen, Yuanyuan Li, Songyang Zhang, Haowen Ran, Qinghui Qi, Cheng Zhang, Huiran Wu, Shuailiang Cao, Haohao Huang, Dake Xiao, Xinzheng Wang, Bohan Li, Jiong Xie, Fangye Li, Qiuying Han, Qiulian Wu, Tao Li, Ailing Li, Jeremy N Rich, Tao Zhou, Jianghong Man.

Glioblastoma (GB) is a highly aggressive brain tumor resistant to chemoradiotherapy, largely due to glioma stem-like cells (GSCs) with robust DNA damage repair capabilities. Here we reveal that GSCs enhance their DNA repair capacity by activating non-homologous end-joining (NHEJ) through upregulation of the apoptosis antagonizing transcription factor (AATF), thereby promoting therapeutic resistance in GB. AATF interacts with XRCC4, a core NHEJ subunit, preventing its degradation via ubiquitin-mediated proteasomal processes. Upon DNA damage, AATF undergoes phosphorylation at Ser189 by ATM, leading to its dissociation from XRCC4 and rapid recruitment of XRCC4 to DNA break sites for efficient NHEJ repair. Moreover, AATF depletion or deficient AATF phosphorylation impedes NHEJ in GSCs, sensitizing GB xenografts to chemoradiotherapy. Additionally, elevated levels of AATF inform poor prognosis in GB patients. Collectively, our findings unveil a crucial role of AATF in XRCC4-mediated NHEJ repair, and underscore targeting AATF as a potential strategy to overcome GB resistance to chemoradiotherapy.

DOI: https://doi.org/10.1038/s41467-025-60228-z
Neuro Oncol. 2025 May 24. pii: noaf115. [Epub ahead of print]

Transient mRNA CAR T cells targeting GD2 provide dose-adjusted efficacy against diffuse midline glioma and high grade glioma models.

Jessica B Foster, Peter J Madsen, Kyra Harvey, Crystal Griffin, Allison Stern, Luke Patterson, Nikhil Joshi, Conor Dickson, Olivia McManus, Ezra Beaubien, Cullen Wilson, David R Beale, Valerie Baubet, Payush N Goel P, Nicholas A Vitanza, Javad Nazarian, Mateusz Koptyra, Phillip B Storm, Adam C Resnick.

   BACKGROUND: Diffuse midline glioma (DMG) and high grade glioma are devastating pediatric central nervous system tumors that remain incurable. Recent chimeric antigen receptor (CAR) T cell studies have shown proof of concept and early signs of efficacy against DMG targeting GD2. Prior work and ongoing clinical trials have focused on using viral vectors to create permanent CAR T cells. However, virally transduced GD2-directed CAR T cells have shown significant neurotoxicity in both pre-clinical models and human trials.
METHODS: We evaluated transient CAR T cells targeting GD2 created with mRNA, assessing for efficacy and safety in cell line, organoid, and in vivo xenograft models with repetitive intratumoral dosing.
RESULTS: We show that mRNA GD2-directed CAR T cells are active against both cell lines and organoid models of DMG and high grade glioma in vitro. Cytotoxicity consistently abates over 9 days, highlighting the potential to avoid toxicity from persistent T cell activity. In both pontine and thalamic DMG xenograft models, repeated doses of mRNA GD2-directed CAR T cells were titrated down to maintain therapeutic effect without causing neurologic toxicity.
CONCLUSIONS: Our results demonstrate the utility of transient mRNA CAR T cells delivered intratumorally to provide effective tumor killing with a defined half-life, allowing for modulation of the dose and potential side effects. We anticipate this study will expand the use of CAR T cell therapy for DMG and other central nervous system tumors and non-malignant disorders, where concern for toxicity from permanently expressing CAR T cells may hinder development.

Keywords:  CAR T cells; brain tumor; diffuse midline glioma; mRNA; pediatric

DOI:  https://doi.org/10.1093/neuonc/noaf115
Neuro Oncol. 2025 May 27. pii: noaf128. [Epub ahead of print]

Polyamine acetylation mediates crosstalk between cancer cells and myeloid cells to promote mesenchymal/plurimetabolic states in glioblastoma.

Ayush B Rana, Timothy M Horton, Vijay S Thakur, Dazhi Wang, Varsha Thakur, Molly Dalzell, Juliano T Freitas, Durga Prasad Gannamedi, Ifeanyichukwu Ogobuiro, Barbara Bedogni, Sakir H Gultekin, Timothy J Garrett, Alejandro V Villarino, Jun Lu, David B Lombard, Ashish H Shah, Scott M Welford.

   BACKGROUND: Metabolic reprogramming in glioblastoma (GBM) is a putative determinant of GBM subtype, malignant cell state and tumor-immune crosstalk. In the present study, we investigated how polyamine metabolic rewiring contributes to the malignant cell-intrinsic and microenvironment-dependent biological processes underpinning GBM subtype classification.
METHODS: Liquid chromatography/tandem mass spectrometry (LC-MS/MS) was used for polyamine quantification in human and murine GBM tumors and cell lines. Through single-cell RNA sequencing, metabolic profiling and additional functional experiments, we dissect the malignant cell-intrinsic and paracrine signaling processes regulated by SAT1 (spermidine/spermine-N1-acetyltransferase1) and its product, N1-acetylspermidine.
RESULTS: We find that polyamine acetylation is elevated in human and murine GBM tumors and contributes to the classification of mesenchymal/plurimetabolic GBM through both regulation of tumor-cell intrinsic glucose metabolism and by facilitating metabolic crosstalk with tumor-associated macrophages/myeloid cells (TAMs). The impact of SAT1 on tumor cell metabolism is mediated, at least in part, by N1-acetylspermdine, the sole polyamine elevated in human and murine tumors. Furthermore, the relatively high levels of N1-acetylspermidine released by GBM is taken up by myeloid cells to promote intracellular polyamine flux, cellular respiration and migration. In vivo, both genetic disruption of polyamine acetylation and pharmacological inhibition of polyamine transport reduced myeloid cell infiltration and sensitized tumors to chemoradiation.
CONCLUSIONS: Collectively, the findings highlight a previously unidentified role for SAT1 and its product, N1-acetylspermidine, in bridging the metabolic activity of tumor cells and tumor-associated macrophages/myeloid cells (TAMs), together promoting mesenchymal/plurimetabolic states and therapeutic resistance in GBM.

Keywords:  Glioblastoma; immune; mesenchymal phenotype; metabolism; polyamines

DOI:  https://doi.org/10.1093/neuonc/noaf128
Cancers (Basel). 2025 May 12. pii: 1631. [Epub ahead of print]17(10):

The Basis for Targeting the Tumor Macrophage Compartment in Glioblastoma Immunotherapy.

Thomas Eckert, Chase Walton, Marcus Bell, Coulter Small, Nathan C Rowland, Charlotte Rivers, Alicia Zukas, Scott Lindhorst, Peter Fecci, Ben A Strickland.

  Background: Glioblastoma (GBM) remains the most aggressive primary brain tumor with limited treatment options. The immunosuppressive tumor microenvironment (TME), largely shaped by tumor-associated macrophages (TAMs), represents a significant barrier to effective immunotherapy. Objective: This review aims to explore the role of TAMs within the TME, highlighting the phenotypic plasticity, interactions with tumor cells, and potential therapeutic targets to enhance anti-tumor immunity. Findings: TAMs constitute a substantial portion of the TME, displaying functional plasticity between immunosuppressive and pro-inflammatory phenotypes. Strategies targeting TAMs include depletion, reprogramming, and inhibition of pro-tumor signaling pathways. Preclinical studies show that modifying TAM behavior can shift the TME towards a pro-inflammatory state, enhancing antitumor immune responses. Clinical trials investigating inhibitors of TAM recruitment, polarization, and downstream signaling pathways reveal promising yet limited results, necessitating further research to optimize approaches. Conclusions: Therapeutic strategics targeting TAM plasticity through selective depletion, phenotypic reprogramming, or modulation of downstream immunosuppressive signals represent promising avenues to overcome GBM-associated immunosuppression. Early clinical trials underscore their safety and feasibility, yet achieving meaningful clinical efficacy requires deeper mechanistic understanding and combinatorial approaches integrating macrophage-direct therapies with existing immunotherapeutic modalities.

Keywords:  glioblastoma; immunotherapy; macrophage polarization; tumor microenvironment; tumor-associated macrophages

DOI:  https://doi.org/10.3390/cancers17101631
Neuro Oncol. 2025 May 28. pii: noaf124. [Epub ahead of print]

Expanding the Immunotherapeutic Toolbox in Glioblastoma: A Safe and Feasible Strategy at the Point of Surgery.

Ghazaleh Tabatabai.

DOI: https://doi.org/10.1093/neuonc/noaf124
Cancer Res. 2025 May 27.

Development of an Anti-CD99 Antibody Enables Targeting of Diffuse Midline Glioma.

Ilango Balakrishnan, Krishna Madhavan, Angela Pierce, Joshua Michlin, Breauna Brunt, Senthilnath Lakshmanachetty, Dong Wang, John DeSisto, Zachary James Nuss, Nathan Davidson, Faye Walker, Ammu Suresh, Andrew Donson, Bridget Sanford, Kenneth L Jones, Etienne P Danis, Siddhartha S Mitra, Adam L Green, Nathan Dahl, Rajeev Vibhakar, Sujatha Venkataraman.

Diffuse midline gliomas (DMGs) are devastating brain tumors that occur primarily in children. The salient feature of these tumors is the presence of a H3K27M mutation (K27M), associated with the worst prognosis. Development of effective strategies for treating K27M+ DMG is desperately needed to help improve patient outcomes. Here, we identified the cell surface antigen CD99 as notably expressed in DMGs, particularly in K27M+ DMGs. The increased expression of CD99 in K27M+ DMGs was a result of the onco-histone K27M mutation. In K27M+ DMG cells, CD99 inactivation impaired tumor growth by inducing cell differentiation. The development of a therapeutic anti-CD99 chimeric antibody, 10D1, with a membrane-proximal binding epitope enabled the evaluation of the antitumor efficacy of targeting CD99 in preclinical models of K27M+ DMG. 10D1 suppressed DMG growth in vitro and in vivo by inducing apoptosis. When combined with radiation treatment, 10D1 exhibited improved antitumor efficacy and prolonged xenograft survival. Together, these findings provide a strong justification for the clinical development of 10D1 as a therapy for targeting CD99 to treat DMGs.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-5027
Oncogene. 2025 May 26.

Post-translational modifications in DNA damage repair: mechanisms underlying temozolomide resistance in glioblastoma.

Yike Chen, Kaikai Ding, Shuyu Zheng, Songting Gao, Xiaohui Xu, Haijian Wu, Fengqi Zhou, Yongjie Wang, Jinfang Xu, Chun Wang, Chenhan Ling, Jing Xu, Lin Wang, Qun Wu, Georgios Giamas, Gao Chen, Jianmin Zhang, Chenggang Yi, Jianxiong Ji.

Temozolomide (TMZ) resistance is one of the critical factors contributing to the poor prognosis of glioblastoma (GBM). As a first-line chemotherapeutic agent for GBM, TMZ exerts its cytotoxic effects through DNA alkylation. However, its therapeutic efficacy is significantly compromised by enhanced DNA damage repair (DDR) mechanisms in GBM cells. Although several DDR-targeting drugs have been developed, their clinical outcomes remain suboptimal. Post-translational modifications (PTMs) in GBM cells play a pivotal role in maintaining the genomic stability of DDR mechanisms, including methylguanine-DNA methyltransferase-mediated repair, DNA mismatch repair dysfunction, base excision repair, and double-strand break repair. This review focuses on elucidating the regulatory roles of PTMs in the intrinsic mechanisms underlying TMZ resistance in GBM. Furthermore, we explore the feasibility of enhancing TMZ-induced cytotoxicity by targeting PTM-related enzymatic to disrupt key steps in PTM-mediated DDR pathways. By integrating current preclinical insights and clinical challenges, this work highlights the potential of modulating PTM-driven networks as a novel therapeutic strategy to overcome TMZ resistance and improve treatment outcomes for GBM patients.

DOI: https://doi.org/10.1038/s41388-025-03454-5
Cancer Cell. 2025 May 27. pii: S1535-6108(25)00216-8. [Epub ahead of print]

Interactions between cancer cells and immune cells drive transitions to mesenchymal-like states in glioblastoma.

Toshiro Hara, Rony Chanoch-Myers, Nathan D Mathewson, Chad Myskiw, Lyla Atta, Lillian Bussema, Stephen W Eichhorn, Alissa C Greenwald, Gabriela S Kinker, Christopher Rodman, L Nicolas Gonzalez Castro, Hiroaki Wakimoto, Orit Rozenblatt-Rosen, Xiaowei Zhuang, Jean Fan, Tony Hunter, Inder M Verma, Kai W Wucherpfennig, Aviv Regev, Mario L Suvà, Itay Tirosh.

DOI: https://doi.org/10.1016/j.ccell.2025.05.007