bims-malgli 2025-02-16 papers

bims-malgli

Biomed News

on Biology of malignant gliomas

Issue of 2025–02–16
fourteen papers selected by
Oltea Sampetrean, Keio University

The AURKA inhibitor alters the immune microenvironment and enhances targeting B7-H3 immunotherapy in glioblastoma.
The promise of mitochondria in the treatment of glioblastoma: a brief review.
A clinically relevant model and method to study necrosis as a driving force in glioma restructuring and progression.
Abnormal Vessels Potentially Accelerate Glioblastoma Proliferation by Inducing the Protumor Activation of Macrophages.
Lack of ST2 aggravates glioma invasiveness, vascular abnormality, and immune suppression.
Interactions Between Ploidy and Resource Availability Shape Clonal Evolution in Glioblastoma.
Therapy enhancing chromosome instability may be advantageous for IDH1 R132H/WT gliomas.
Immuno-epidemiologic mapping of HLA diversity across glioma patient cohorts.
Identifying appropriate external control datasets in support of future glioblastoma clinical trials leveraging external data.
High-throughput in vitro drug screening and in vivo studies identify fenretinide as a brain-penetrant DMG therapeutic.
TRAF3 loss protects glioblastoma cells from lipid peroxidation and immune elimination via dysregulated lipid metabolism.
Identification of Urinary Metabolic Biomarkers for H3K27M Mutation Diagnosis in Brainstem Gliomas.
STAT3-controlled CHI3L1/SPP1 positive feedback loop demonstrates the spatial heterogeneity and immune characteristics of glioblastoma.
Individualized patient tumor organoids faithfully preserve human brain tumor ecosystems and predict patient response to therapy.

JCI Insight. 2025 Feb 10. pii: e173700. [Epub ahead of print]

The AURKA inhibitor alters the immune microenvironment and enhances targeting B7-H3 immunotherapy in glioblastoma.

Jinqiu Liu, Yuxuan Deng, Zhuonan Pu, Yazhou Miao, Zhaonian Hao, Herui Wang, Shaodong Zhang, Hanjie Liu, Jiejun Wang, Yifan Lv, Boyi Hu, Hong Wan, Zhengping Zhuang, Tai Sun, Shuyu Hao, Nan Ji, Jie Feng.

  Glioblastoma (GBM) is one of the most lethal adult brain tumors with limited effective therapeutic options. Immunotherapy targeting B7-H3 (CD276) has shown promising efficacy in the treatment of gliomas. However, the response to this treatment varies among glioma patients due to individual differences. It's necessary to find an effective strategy to improve the efficacy of targeting B7-H3 immunotherapy for non-responders. In this study, we demonstrated a strong correlation between aurora kinase A (AURKA) and CD276 expression in glioma tissue samples. Additionally, both AURKA knockdown and overexpression resulted in parallel changes in B7-H3 expression levels in glioma cells. Mechanistically, AURKA elevated B7-H3 expression by promoting epidermal growth factor receptor (EGFR) phosphorylation, which was validated in glioma cell lines and primary GBM cells. What's more, the combination of AURKA inhibitor (alisertib) and anti-B7-H3 antibody markedly reduced tumor size and promoted CD8+ T cell infiltration and activation in mouse orthotopic syngeneic glioma models. To our knowledge, this study is the first to demonstrate AURKA-mediated B7-H3 upregulation in glioma cells; moreover, it proposes a promising therapeutic strategy combining the AURKA inhibitor alisertib with B7-H3-specific blocking mAbs.

Keywords:  Cancer immunotherapy; Oncology; Therapeutics

DOI:  https://doi.org/10.1172/jci.insight.173700
Discov Oncol. 2025 Feb 09. 16(1): 142

The promise of mitochondria in the treatment of glioblastoma: a brief review.

Zhuo Liang, Songyun Zhao, Yuankun Liu, Chao Cheng.

  Glioblastoma (GBM) is a prevalent and refractory type of brain tumor. Over the past two decades, there have been minimal advancements in GBM therapy. The current standard treatment involves surgical excision followed by radiation and chemotherapy. Compared to other tumors, GBM is more challenging to treat due to the presence of glioma stem-like cells (GSCs) and the blood-brain barrier, resulting in an extremely low survival rate. Mitochondria play a critical role in tumor respiration, metabolism, and multiple signaling pathways involved in tumor formation, progression, and cell apoptosis. Consequently, mitochondria represent promising targets for developing novel anticancer agents, including those targeting oxidative phosphorylation, reactive oxygen species (ROS), mitochondrial transfer, and mitophagy. This review outlines the mitochondrial-related therapeutic targets in GBM, highlighting the potential of mitochondria as a target for GBM treatment.

Keywords:  Glioblastoma; Mitochondria; Mitochondrial autophagy; Mitochondrial metastasis; Oxidative phosphorylation; ROS

DOI:  https://doi.org/10.1007/s12672-025-01891-y
Proc Natl Acad Sci U S A. 2025 Feb 18. 122(7): e2416024122

A clinically relevant model and method to study necrosis as a driving force in glioma restructuring and progression.

Jiabo Li, Ling-Kai Shih, Steven M Markwell, Cheryl L Olson, David P Sullivan, Constadina Arvanitis, James L Ross, Nicolas G Lam, Hannah Nuszen, Dolores Hambardzumyan, Oren J Becher, Daniel J Brat.

  All glioblastoma (GBM) molecular subsets share the common trait of accelerated progression following necrosis, which cannot be adequately explained by cellular proliferation arising from accumulated genetic alterations. Counter to dogma that "cancer outgrows its blood supply," we suggest that development of necrosis is not merely a consequence of aggressive neoplastic growth but could be a contributing force causing tumor microenvironment (TME) restructuring and biologic progression. Mechanisms related to necrotic contributions are poorly understood due to a lack of methods to study necrosis as a primary variable. To reveal spatiotemporal changes related to necrosis directly, we developed a mouse model and methodology designed to induce clinically relevant thrombotic vaso-occlusion within GBMs in an immunocompetent RCAS/tv-a mouse model to study TME restructuring by intravital microscopy and demonstrate its impact on glioma progression. Diffuse high-grade gliomas are generated by introducing RCAS-PDGFB-RFP and RCAS-Cre in a Nestin/tv-a; TP53fl/fl PTENfl/fl background mouse. We then photoactivate Rose Bengal in specific, targeted blood vessels within the glioma to induce thrombosis, hypoxia, and necrosis. Following induced necrosis, GBMs undergo rapid TME restructuring and radial expansion, with immunosuppressive bone marrow-derived, tumor-associated macrophages (TAMs) and glioma stem cells (GSCs) increasing dramatically in the perinecrotic niche. Collectively, this model introduces necrosis as the primary variable and captures glioma TME and growth dynamics in a manner that will facilitate therapeutic development to antagonize these mechanisms of progression.

Keywords:  glioblastoma; glioma stem cell; mouse model; necrosis; tumor-associated macrophage

DOI:  https://doi.org/10.1073/pnas.2416024122
Cancer Sci. 2025 Feb 07.

Abnormal Vessels Potentially Accelerate Glioblastoma Proliferation by Inducing the Protumor Activation of Macrophages.

Hiroaki Matsuzaki, Keitaro Kai, Yoshihiro Komohara, Hiromu Yano, Cheng Pan, Yukio Fujiwara, Rin Yamada, Ai Iwauchi, Nei Fukasawa, Toshihide Tanaka, Masayuki Shimoda, Hiroshi Watanabe, Toru Maruyama, Toru Takeo, Yoshiki Mikami, Akitake Mukasa.

  Glioblastoma (GBM) involves disruptions in the blood-brain barrier (BBB) and alterations in the immune microenvironment, including the activation of glioma-associated macrophages (GAMs). Vascular endothelial growth factor inhibitors, commonly used in recurrent GBM treatment, can influence these processes. This study investigates the relationship between BBB disruption and GAM activation, focusing on plasmalemma vesicle-associated protein (PLVAP), a marker of BBB disruption, and α1-acid glycoprotein (AGP), an inflammatory protein implicated in tumor progression. PLVAP expression was analyzed by immunohistochemistry (IHC) in human GBM samples to determine correlations with tumor grade, proliferation, and GAM activation. Pre- and post-bevacizumab treatment GBM samples were compared to assess changes in BBB integrity and macrophage activity. AGP's role in GAM activation was studied through in vitro assays and glioma implantation in AGP knockout mice, with assessments of tumor growth and angiogenesis. Results showed elevated PLVAP expression in higher-grade gliomas, correlating with increased tumor proliferation and GAM activation, particularly around PLVAP-positive vessels. Bevacizumab treatment reduced PLVAP expression and macrophage activity. AGP localized to regions of BBB disruption, promoting macrophage-mediated tumor growth in vitro. AGP knockout mice demonstrated reduced angiogenesis and prolonged survival. Spatial analysis revealed increased expression of macrophage-inducing molecules near PLVAP-positive vessels. These findings suggest PLVAP as a marker of BBB disruption and glioma malignancy. AGP, associated with BBB leakage, contributes to GAM activation and tumor progression, highlighting its potential as a therapeutic target for GBM.

Keywords:  blood−brain barrier; glioblastoma; glioma‐associated macrophage; plasmalemma vesicle‐associated protein; tumor‐associated macrophage; α1‐acid glycoprotein

DOI:  https://doi.org/10.1111/cas.70014
Neurooncol Adv. 2025 Jan-Dec;7(1):7(1): vdaf010

Lack of ST2 aggravates glioma invasiveness, vascular abnormality, and immune suppression.

Grzegorz Wicher, Ananya Roy, Alessandra Vaccaro, Kalyani Vemuri, Mohanraj Ramachandran, Tommie Olofsson, Rebeca-Noemi Imbria, Mattias Belting, Gunnar Nilsson, Anna Dimberg, Karin Forsberg-Nilsson.

Background: Glioblastoma (GBM) is the most common primary malignant brain tumor in adults, characterized by aggressive growth and a dismal prognosis. Interleukin-33 (IL-33) and its receptor ST2 have emerged as regulators of glioma growth, but their exact function in tumorigenesis has not been deciphered. Indeed, previous studies on IL-33 in cancer have yielded somewhat opposing results as to whether it is pro- or anti-tumorigenic.
Methods: IL-33 expression was assessed in a GBM tissue microarray and public databases. As in vivo models we used orthotopic xenografts of patient-derived GBM cells, and syngenic models with grafted mouse glioma cells.
Results: We analyzed the role of IL-33 and its receptor ST2 in nonmalignant cells of the glioma microenvironment and found that IL-33 levels are increased in cells surrounding the tumor. Protein complexes of IL-33 and ST2 are mainly found outside of the tumor core. The IL-33-producing cells consist primarily of oligodendrocytes. To determine the function of IL-33 in the tumor microenvironment, we used mice lacking the ST2 receptor. When glioma cells were grafted to ST2-deficient mouse brains, the resulting tumors exhibited a more invasive growth pattern, and are associated with poorer survival, compared to wild-type mice. Tumors in ST2-deficient hosts are more invasive, with increased expression of extracellular matrix remodeling enzymes and enhanced tumor angiogenesis. Furthermore, the absence of ST2 leads to a more immunosuppressive environment.
Conclusions: Our findings reveal that glia-derived IL-33 and its receptor ST2 participate in modulating tumor invasiveness, tumor vasculature, and immunosuppression in glioma.

DOI: https://doi.org/10.1093/noajnl/vdaf010
Cancer Res. 2025 Feb 11.

Interactions Between Ploidy and Resource Availability Shape Clonal Evolution in Glioblastoma.

Zuzanna Nowicka, Frederika Rentzeperis, Vural Tagal, Jamie K Teer, Didem Ilter, Richard J Beck, Jackson P Cole, Ana M Forero Pinto, Joanne D Tejero, Elisa Scanu, Thomas Veith, William Dominguez-Viqueira, Konstantin Maksin, Francisco M Carrillo-Perez, Olivier Gevaert, Xiaonan Xu, Florian A Karreth, Mahmoud A Abdalah, Giada Fiandaca, Stefano Pasetto, Sandhya Prabhakaran, Andrew Schultz, Awino Maureiq E Ojwang', Jill S Barnholtz-Sloan, Joaquim M Farinhas, Ana P Gomes, Parag Katira, Noemi Andor.

Glioblastoma (GBM) is the most aggressive form of primary brain tumor. The infiltrative nature of GBM makes complete surgical resection impossible. The selective forces that govern gliomagenesis are strong, shaping the composition of tumor cells during the initial progression to malignancy with late consequences for invasiveness and therapy response. Here, we developed a mathematical model that incorporates ploidy level and the nature of the brain tissue microenvironment to simulate the growth and invasion of GBM and used the model to make inferences about GBM initiation and response to standard-of-care treatment. The spatial distribution of resource access in the brain was approximated through integration of in silico modeling, multi-omics data, and image analysis of primary and recurrent GBM. The in silico results suggested that high ploidy cells transition faster from oxidative phosphorylation to glycolysis than low ploidy cells because they are more sensitive to hypoxia. Between surgeries, simulated tumors with different ploidy compositions progressed at different rates; however, whether higher ploidy predicted fast recurrence was a function of the brain microenvironment. Historical data supported the dependence on available resources in the brain, as shown by a significant correlation between the median oxygen levels in human tissues and the median ploidy of cancers that arise in the respective tissues. Taken together, these findings suggest that availability of metabolic substrates in the brain drives different cell fate decisions for cells with different ploidy, thereby modulating both gliomagenesis and GBM recurrence.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-0401
NAR Cancer. 2025 Mar;7(1): zcaf003

Therapy enhancing chromosome instability may be advantageous for IDH1 R132H/WT gliomas.

Nikolay V Goncharov, Ivan N Baklanov, Valeriia S Gulaia, Anastasiia P Shuliak, Daria V Lanskikh, Valeriia M Zhmenia, Mikhail E Shmelev, Nikita A Shved, Jing Wu, Mikhail Liskovykh, Vladimir Larionov, Natalay Kouprina, Vadim V Kumeiko.

Recently revised brain tumor classification suggested a glioma treatment strategy that takes into consideration molecular variants in IDH1 and TP53 marker genes. While pathogenic variants of IDH1 and TP53 can be accompanied by chromosomal instability (CIN), the impact of IDH1 and TP53 mutations on genome stability remains unstudied. Elevated CIN might provide therapeutic targets, based on synergistic effects of chemotherapy with CIN-inducing drugs. Using an assay based on human artificial chromosomes, we investigated the impact of common glioma missense mutations in IDH1 and TP53 on chromosome transmission and demonstrated that IDH1R132H and TP53R248Q variants elevate CIN. We next found enhanced CIN levels and the sensitivity of IDH1 R132H/WT and TP53 R248Q/R248Q genotypes, introduced into U87 MG glioma cells by CRISPR/Cas9, to different drugs, including conventional temozolomide. It was found that U87 MG cells carrying IDH1 R132H/WT exhibit dramatic sensitivity to paclitaxel, which was independently confirmed on cell cultures derived from patients with naturally occurring IDH1 R132H/WT. Overall, our results suggest that the development of CIN-enhancing therapy for glioma tumors with the IDH1 R132H/WT genotype could be advantageous for adjuvant treatment.

DOI: https://doi.org/10.1093/narcan/zcaf003
Neuro Oncol. 2025 Feb 14. pii: noaf040. [Epub ahead of print]

Immuno-epidemiologic mapping of HLA diversity across glioma patient cohorts.

Zujian Xiong, Kyle M Walsh, Chaim T Sneiderman, Michal Nisnboym, Costas G Hadjipanayis, Sameer Agnihotri, Todd N Eagar, Hong Wang, Ian F Pollack, Thomas G Forsthuber, Xuejun Li, Itay Raphael, Gary Kohanbash.

   BACKGROUND: Individual-level characteristics underlying population-level variation in glioma risk and outcomes remain incompletely understood. Cancer immunosurveillance, host immunity, and some immunotherapies center on the ability of an individual's immune cells to recognize antigen epitopes presented on MHC molecules. Inter-individual variation in HLA alleles can elicit distinct repertoires of tumor antigen for presentation to immune cells. Therefore, HLA alleles may impact glioma incidence and prognosis.
METHODS: HLA class I (HLA-I) alleles were identified using sequencing data from four large glioma cohorts and healthy cohorts, matched on ancestry, and race- and age-matched imputed cohorts developed by the Hardy-Weinberg equilibrium were referred to determine odds ratio incidence estimated by logistic regression. HLA prognostication was quantified by Cox regression.
RESULTS: We analyzed 1,215 cases of glioma patients from non-Hispanic Whites and Asians. The HLA-I allelic frequencies of gliomas generally corresponded to their distribution within each race. However, specific HLA-I alleles were significantly associated with glioma incidence and prognosis, which differ between races but were independent of age and sex. Notably, non-Hispanic White glioma patients exhibited greater HLA homozygosity rates compared with race-matched controls. HLA-C01:02 and HLA-C07:02 displayed opposing effects on glioma prognosis between races. The distinct effects were associated with their capability of presenting specific mutations that appeared at the initial or late phase of glioma progression.
CONCLUSIONS: Expression of specific HLA-I alleles are associated with glioma incidence and prognosis within race. HLA-I-homozygosity is a risk factor for glioma in non-Hispanic Whites. These findings may guide development of precision-guided immunotherapies for glioma.

Keywords:  HLA-I; glioma; homozygosity; incidence; prognosis

DOI:  https://doi.org/10.1093/neuonc/noaf040
Neuro Oncol. 2025 Feb 08. pii: noaf031. [Epub ahead of print]

Identifying appropriate external control datasets in support of future glioblastoma clinical trials leveraging external data.

Rifaquat Rahman, Steffen Ventz, Robert Redd, Geoffrey Fell, Yujue Tan, Peter Orio, Kirk Tanner, Patrick Y Wen, Lorenzo Trippa.

   BACKGROUND: Recent interest in leveraging external data for clinical trial design and analysis in glioblastoma has raised questions on the identification of appropriate data to use as external controls for future trials. We perform a comprehensive analysis assessing candidate sources of external data and comparing clinical trial and real-world datasets in newly diagnosed glioblastoma.
METHODS: Individual patient-level data (PLD) from several clinical trials, a large academic institutional database and a registry (National Cancer Database) were used for analysis of patients receiving standard of care radiation with concurrent and adjuvant temozolomide. Data summaries from randomized trials 2012-2022 were analyzed to account for trials without available PLD. Multivariable modeling was employed to compare survival across datasets.
RESULTS: In total, 8 datasets with PLD for 3061 patients with newly diagnosed glioblastoma treated with standard chemoradiation were analyzed. Patients on trials were younger (age<60:64% vs. 48%,p<0.001) and had higher KPS (KPS>90:58% vs. 48%,p<0.001) compared to non-trial patients. Patients in clinical trials exhibited inferior survival relative to non-trial patients (HR 1.30,95%CI 1.13-1.48,p<0.001) after adjustment for age, sex, KPS, extent of resection and MGMT methylation status. In assessment of data summaries of 19 randomized trials, there was no detectable time-trend toward improved outcomes 2012-2022.
CONCLUSIONS: In newly diagnosed glioblastoma patients treated with standard of care chemoradiation, there were significant differences between trial datasets and real-world datasets but no evidence of a trial effect benefit from trial participation. After adjustment of relevant covariates, there was no evidence of temporal drift of improved survival over the last decade.

Keywords:  clinical trials; drug development; external control arms; glioblastoma

DOI:  https://doi.org/10.1093/neuonc/noaf031
Neuro Oncol. 2025 Feb 12. pii: noaf035. [Epub ahead of print]

High-throughput in vitro drug screening and in vivo studies identify fenretinide as a brain-penetrant DMG therapeutic.

Dannielle H Upton, Jie Liu, Sandra M George, Santosh Valvi, Caitlin Ung, Benjamin S Rayner, Anjana Gopalakrishnan, Ruby Pandher, Aaminah Khan, Pooja Venkat, Chelsea Mayoh, Holly Holliday, Nicole Yeung, Hieu Nguyen, Laura Franshaw, Anahid Ehteda, Han Shen, Giovanna Farruggia, Isabella Orienti, C Patrick Reynolds, Maria Tsoli, David S Ziegler.

   BACKGROUND: Diffuse midline glioma, characterised by H3K27 alteration (DMG), is the predominant high-grade glioma in children. It commonly originates in the brainstem, yet effective treatments for these patients remain elusive.
METHODS: To identify novel therapies for DMG, we conducted high-throughput drug screens (HTS) using biologically active, clinically approved compounds against DMG neurospheres. Multiple primary DMG cultures were utilised in conjunction with in vitro cytotoxicity and clonogenic assays to validate the efficacy of top compounds. Molecularly diverse patient-derived and transgenic DMG orthotopic models were employed to assess therapeutic efficacy alongside pharmacokinetic and immunohistochemical analyses. Mechanistic studies, including RNA sequencing, western blotting, and flow cytometry, were conducted to elucidate the antitumour efficacy of the most promising compound, fenretinide, in DMG cells.
RESULTS: Through HTS, six compounds were identified and validated for their potent cytotoxic activity. However, most of these compounds failed to improve survival in an orthotopic Diffuse Midline Glioma (DMG) model due to limited blood-brain barrier (BBB) penetration. In contrast, fenretinide exhibited effective BBB penetration, significantly enhancing the survival of tumour-bearing animals. Mechanistic studies revealed that fenretinide increased reactive oxygen species (ROS) generation and induced apoptosis by inhibiting PDGFRα. RNA-sequencing further elucidated that fenretinide upregulates the Unfolded Protein Response (UPR) and endoplasmic reticulum (ER) stress pathways while downregulating neurogenesis. The in vivo antitumour efficacy of two fenretinide formulations was demonstrated in PDGFRα-amplified and transgenic DMG models.
CONCLUSION: This comprehensive study has identified new DMG therapeutic vulnerabilities and highlights fenretinide as a brain-penetrant, anti-DMG agent.

Keywords:  DMG; PDX; fenretinide; high-throughput screening; therapeutic

DOI:  https://doi.org/10.1093/neuonc/noaf035
J Clin Invest. 2025 Feb 11. pii: e178550. [Epub ahead of print]

TRAF3 loss protects glioblastoma cells from lipid peroxidation and immune elimination via dysregulated lipid metabolism.

Yu Zeng, Liqian Zhao, Kunlin Zeng, Ziling Zhan, Zhengming Zhan, Shangbiao Li, Hongchao Zhan, Peng Chai, Cheng Xie, Shengfeng Ding, Yuxin Xie, Li Wang, Cuiying Li, Xiaoxia Chen, Daogang Guan, Enguang Bi, Jian-You Liao, Fan Deng, Xiaochun Bai, Ye Song, Aidong Zhou.

  Glioblastoma (GBM) is a highly aggressive form of brain tumor characterized by dysregulated metabolism. Increased fatty acid oxidation (FAO) protects tumor cells from lipid peroxidation-induced cell death, although the precise mechanisms involved remain unclear. Herein, we report that loss of tumor necrosis factor receptor-associated factor 3 (TRAF3) in GBM critically regulates lipid peroxidation and tumorigenesis by controlling the oxidation of polyunsaturated fatty acids (PUFAs). TRAF3 is frequently repressed in GBM due to promoter hypermethylation. TRAF3 interacts with enoyl-CoA hydratase 1 (ECH1), an enzyme catalyzing the isomerization of unsaturated fatty acids (UFAs), and mediates K63-linked ubiquitination of ECH1 at Lys214. ECH1 ubiquitination impedes TOMM20-dependent mitochondrial translocation of ECH1, which otherwise promotes the oxidation of UFAs, preferentially the PUFAs, and limits lipid peroxidation. Overexpression of TRAF3 enhances the sensitivity of GBM to ferroptosis and anti-PD-L1 immunotherapy in mice. Thus, the TRAF3-ECH1 axis plays a key role in the metabolism of PUFAs, and is crucial for lipid peroxidation damage and immune elimination in GBM.

Keywords:  Brain cancer; Cancer immunotherapy; Cell biology; Fatty acid oxidation; Metabolism

DOI:  https://doi.org/10.1172/JCI178550
Neuro Oncol. 2025 Feb 14. pii: noaf038. [Epub ahead of print]

Identification of Urinary Metabolic Biomarkers for H3K27M Mutation Diagnosis in Brainstem Gliomas.

Xiaoou Li, Wei Sun, Zhengguang Guo, Feng Qi, Tian Li, Yujin Wang, Mingxin Zhang, Aiwei Wang, Zhuang Jiang, Luyang Xie, Yiying Mai, Yi Wang, Zhen Wu, Nan Ji, Yang Zhang, Liwei Zhang.

   BACKGROUND: Brainstem gliomas (BSGs) harboring a histone 3 lysine27-to-methionine (H3K27M) mutation represent one of the deadliest brain tumors with a dismal prognosis, as they exhibit a much worse response to therapy compared to the wildtype BSGs. Early non-invasive recognition of the H3K27M mutation is paramount for clinical decision-making in treating BSGs.
METHODS: Plasma and urine samples were prospectively collected from BSG patients before biopsy or surgical resection and were chronologically divided into discovery, test, and validation cohorts. Utilizing the discovery and test cohort samples, an untargeted metabolomic strategy was exploited to identify candidate metabolite biomarkers, related to the H3K27M mutation. The candidate biomarkers were validated in the validation cohort with a targeted metabolomic method.
RESULTS: Differential metabolomic profiles were detected between the H3K27M-mutant and wild-type BSGs in both the plasma and urine, the metabolomic changes were more dramatic in urine than in plasma. After rigorous screening for candidate biomarkers and validation with a targeted metabolomic approach, three metabolites, nomilin, Lys-Leu, and hawkinsin, emerged as significantly elevated biomarkers in H3K27M-mutant BSG urine samples. The biomarker panel combining the three metabolites had a diagnostic area under the curve (AUC) of approximately 75%. Furthermore, the biomarker panel improved the prediction accuracy of radiomics/clinical models to an AUC value high as 93.38%.
CONCLUSIONS: A urinary metabolite biomarker panel that exhibited high accuracy for non-invasive prediction of the H3K27M mutation status in BSG patients was identified. This panel has the potential to improve the predictive performance of current radiomics models or clinical features.

Keywords:  BSGs; H3K27M; brainstem gliomas; metabolomics; urine

DOI:  https://doi.org/10.1093/neuonc/noaf038
Dev Cell. 2025 Feb 07. pii: S1534-5807(25)00034-6. [Epub ahead of print]

STAT3-controlled CHI3L1/SPP1 positive feedback loop demonstrates the spatial heterogeneity and immune characteristics of glioblastoma.

Wanli Yu, Shikai Gui, Lunshan Peng, Haitao Luo, Jiabao Xie, Juexian Xiao, Yimuran Yilamu, Yi Sun, Shihao Cai, Zujue Cheng, Zhennan Tao.

  Proneural-mesenchymal transition (PMT) is a phenotypic alteration and contributes to the malignant progression of glioblastoma (GBM). Macrophages, as a main infiltrating component of the tumor immune microenvironment (TIM), control the biological processes of PMT; however, the mechanisms driving this process remain largely unknown. Here, the overall landscape of tumor and nontumor cells was described by scMulti-omics technology. Then, we demonstrated that chitinase-3-like protein 1 (CHI3L1) played a critical role in maintaining mesenchymal (MES) status and reprogramming macrophage phenotype using C57BL/6 and NSG mice models derived from PN20 cells. Mechanistically, osteopontin (OPN)/ITGB1 maintained the activation of nuclear factor κB (NF-κB) and signal transducer and activator of transcription 3 (STAT3) pathways by establishing a positive feedback loop with the CHI3L1-STAT3 axis, resulting in PMT. CHI3L1 enhanced the phosphorylation, nuclear localization, and transcriptional activity of STAT3 via directly binding its coiled-coil domain (CCD). Importantly, we screened and validated that hygromycin B (HB), an inhibitor of the STAT3-CCD domain, disrupted the CHI3L1-STAT3 interaction, thereby reducing the tumor burden in vitro and in vivo.

Keywords:  CHI3L1, SPP1; PMT; glioblastoma; macrophages; scMulti-omics

DOI:  https://doi.org/10.1016/j.devcel.2025.01.014
Cell Stem Cell. 2025 Feb 05. pii: S1934-5909(25)00002-5. [Epub ahead of print]

Individualized patient tumor organoids faithfully preserve human brain tumor ecosystems and predict patient response to therapy.

Tianping Peng, Xiujian Ma, Wei Hua, Changwen Wang, Youjun Chu, Meng Sun, Valentina Fermi, Stefan Hamelmann, Katharina Lindner, Chunxuan Shao, Julia Zaman, Weili Tian, Yue Zhuo, Yassin Harim, Nadja Stöffler, Linda Hammann, Qungen Xiao, Xiaoliang Jin, Rolf Warta, Catharina Lotsch, Xuran Zhuang, Yuan Feng, Minjie Fu, Xin Zhang, Jinsen Zhang, Hao Xu, Fufang Qiu, Liqian Xie, Yi Zhang, Wei Zhu, Zunguo Du, Lorena Salgueiro, Mark Schneider, Florian Eichhorn, Arthur Lefevre, Stefan Pusch, Valery Grinevich, Miriam Ratliff, Sonja Loges, Lukas Bunse, Felix Sahm, Yangfei Xiang, Andreas Unterberg, Andreas von Deimling, Michael Platten, Christel Herold-Mende, Yonghe Wu, Hai-Kun Liu, Ying Mao.

  Tumor organoids are important tools for cancer research, but current models have drawbacks that limit their applications for predicting response to therapy. Here, we developed a fast, efficient, and complex culture system (IPTO, individualized patient tumor organoid) that accurately recapitulates the cellular and molecular pathology of human brain tumors. Patient-derived tumor explants were cultured in induced pluripotent stem cell (iPSC)-derived cerebral organoids, thus enabling culture of a wide range of human tumors in the central nervous system (CNS), including adult, pediatric, and metastatic brain cancers. Histopathological, genomic, epigenomic, and single-cell RNA sequencing (scRNA-seq) analyses demonstrated that the IPTO model recapitulates cellular heterogeneity and molecular features of original tumors. Crucially, we showed that the IPTO model predicts patient-specific drug responses, including resistance mechanisms, in a prospective patient cohort. Collectively, the IPTO model represents a major breakthrough in preclinical modeling of human cancers, which provides a path toward personalized cancer therapy.

Keywords:  brain metastasis; glioblastoma; patient tumor organoid; predictive patient model; temozolomide; tumor heterogeneity

DOI:  https://doi.org/10.1016/j.stem.2025.01.002