Acta Neuropathologica Communications最新文献

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MYC promotes group 3 medulloblastoma cell proliferation and alleviates ROS-induced cell death by upregulating transketolase. MYC通过上调转酮醇酶促进3组髓母细胞瘤细胞增殖,减轻ros诱导的细胞死亡。
IF 6.2 2区 医学
Acta Neuropathologica Communications Pub Date : 2025-06-28 DOI: 10.1186/s40478-025-02051-7
Shizun Wang, Dan Zhang, Chunlong Wang, Yuqin Liu
{"title":"MYC promotes group 3 medulloblastoma cell proliferation and alleviates ROS-induced cell death by upregulating transketolase.","authors":"Shizun Wang, Dan Zhang, Chunlong Wang, Yuqin Liu","doi":"10.1186/s40478-025-02051-7","DOIUrl":"10.1186/s40478-025-02051-7","url":null,"abstract":"<p><p>Medulloblastoma is a common embryonic malignant tumor in children. Patients with Group 3 medulloblastoma exhibit the poorest prognosis among all subgroups, and approximately 20% of these patients carry an amplification of MYC. Metabolic reprogramming, a hallmark of cancer, includes the pentose phosphate pathway (PPP) as a branch of glucose metabolism, providing cells with ribose-5-phosphate (R5P) and nicotinamide adenine dinucleotide phosphate (NADPH). The role of PPP in medulloblastoma remains unclear. In this study, we utilized transcriptomic data to identify that high expression of transketolase (TKT) correlates with worse overall survival (OS) in Group 3 patients. We found that TKT promotes proliferation of Group 3 medulloblastoma cell line cells both in vitro and in vivo. Additionally, TKT enhances R5P synthesis, increasing the proportion of S-phase cells and promoting proliferation. TKT also facilitates NADPH synthesis, which reduces intracellular reactive oxygen species (ROS) levels, inhibits ROS-induced cell death, and strengthens cellular resistance to ROS-induced injury. Subsequently, we demonstrated that inhibition of MYC leads to decreased TKT protein levels, and MYC promotes cell proliferation and suppresses cell death via TKT. Chromatin immunoprecipitation-quantitative real-time polymerase chain reaction (ChIP-qPCR) confirmed that employing the antibody targeting MYC enables the immunoprecipitation of DNA localized to the promoter region of TKT. Using luciferase assay and western blot, we verified that MYC and specificity protein 1 (SP1) co-regulate the transcription of TKT and consequently elevates TKT protein levels. Collectively, our study reports that MYC facilitates the proliferation of Group 3 medulloblastoma cells and mitigates ROS-induced damage through TKT, suggesting TKT as a potential therapeutic target for MYC-driven Group 3 medulloblastoma.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"139"},"PeriodicalIF":6.2,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12205496/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144525933","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Copper supplementation mitigates Parkinson-like wild-type SOD1 pathology and nigrostriatal degeneration in a novel mouse model. 在一种新的小鼠模型中,铜补充剂减轻了帕金森样野生型SOD1病理和黑质纹状体变性。
IF 6.2 2区 医学
Acta Neuropathologica Communications Pub Date : 2025-06-25 DOI: 10.1186/s40478-025-02048-2
Benjamin D Rowlands, Benjamin G Trist, Connor Karozis, Greta Schaffer, David Mor, Richard Harwood, Sarah A Rosolen, Veronica Cottam, Freyja Persson-Carboni, Miriam Richardson, Anne A Li, Michael P Gotsbacher, Amr H Abdeen, Rachel Codd, Kay L Double
{"title":"Copper supplementation mitigates Parkinson-like wild-type SOD1 pathology and nigrostriatal degeneration in a novel mouse model.","authors":"Benjamin D Rowlands, Benjamin G Trist, Connor Karozis, Greta Schaffer, David Mor, Richard Harwood, Sarah A Rosolen, Veronica Cottam, Freyja Persson-Carboni, Miriam Richardson, Anne A Li, Michael P Gotsbacher, Amr H Abdeen, Rachel Codd, Kay L Double","doi":"10.1186/s40478-025-02048-2","DOIUrl":"10.1186/s40478-025-02048-2","url":null,"abstract":"<p><p>Misfolded wild-type superoxide dismutase 1 (disSOD1) protein is implicated in the death of substantia nigra (SN) dopamine neurons in Parkinson disease. Regionally reduced copper availability, and subsequent reduced copper binding to SOD1, is a key factor driving the development of this pathology, suggesting brain copper supplementation may constitute an effective means of preventing its formation. We evaluated whether the blood-brain-barrier-permeable copper delivery drug, CuATSM, attenuated the misfolding and deposition of wild-type disSOD1 and associated neuron death in a novel mouse model that expresses this pathology. These factors were profiled using proteomic and elemental mass spectrometry, together with biochemical and histological workflows. We demonstrated copper supplementation corrects altered post-translational modifications on soluble SOD1 and improves the enzymatic activity of the protein in the brains of these animals. These changes were associated with a significant reduction in disSOD1 pathology and preservation of dopamine neurons in the SN, which were highly correlated with tissue copper levels. Our data position wild-type disSOD1 pathology as a novel drug target for Parkinson disease and suggest that brain copper supplementation may constitute an effective means of slowing SN dopamine neuron death in this disorder.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"133"},"PeriodicalIF":6.2,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12188662/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144493319","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Robust molecular subgrouping and reference-free aneuploidy detection in medulloblastoma using low-depth whole genome bisulfite sequencing. 利用低深度全基因组亚硫酸盐测序检测髓母细胞瘤的强大分子亚群和无参考非整倍体。
IF 6.2 2区 医学
Acta Neuropathologica Communications Pub Date : 2025-06-24 DOI: 10.1186/s40478-025-02049-1
Dean Thompson, Jemma Castle, Martin Sill, Stefan M Pfister, Simon Bailey, Debbie Hicks, Steven C Clifford, Edward C Schwalbe
{"title":"Robust molecular subgrouping and reference-free aneuploidy detection in medulloblastoma using low-depth whole genome bisulfite sequencing.","authors":"Dean Thompson, Jemma Castle, Martin Sill, Stefan M Pfister, Simon Bailey, Debbie Hicks, Steven C Clifford, Edward C Schwalbe","doi":"10.1186/s40478-025-02049-1","DOIUrl":"10.1186/s40478-025-02049-1","url":null,"abstract":"<p><p>Medulloblastoma comprises four principal molecular disease groups and their component subgroups, each with distinct molecular and clinical features. Group assignment is currently achieved diagnostically using Illumina DNA methylation microarray. Whole-genome sequencing (WGS) capacity is rapidly expanding in the clinical setting and the development of platform-independent, sequence-based assays of molecular group offers significant potential. Specifically, whole-genome bisulfite sequencing (WGBS) enables assessment of genome-wide methylation status at single-base resolution, however its routine application has been limited by high DNA input requirements, cost, and a lack of pipelines tailored to more rapidly-acquired and cost-effective low-depth (< 10x) sequencing data. We utilised WGBS data for 69 medulloblastomas, comprising 35 in-house low-depth (~ 10x) and 34 publicly available high-depth (~ 30x) samples, alongside cerebellar controls (n = 8), all with matched DNA methylation microarray data. We assessed quality (QC) and imputation approaches using low-pass WGBS data, assessed inter-platform correlation and identified molecular groups and subgroups by directly integrating matched/associated loci from WGBS sample data with the MNP classifier probeset. We further assessed and optimised reference-free aneuploidy detection using low-pass WGBS and assessed concordance with microarray-derived calls. We developed and optimised pipelines for processing, QC, and analysis of low-pass WGBS data, suitable for routine molecular subgrouping and reference-free aneuploidy assessment. We demonstrate that low-pass WGBS data can (i) be integrated into existing array-trained models with high assignment probabilities for both principal molecular groups (97% concordance) and molecular subgroups (94.2% concordance), and (ii) detect clinically relevant focal copy number changes, including SNCAIP, with greater sensitivity than microarray approaches. Low-pass WGBS performs equivalently to array-based methods at comparable cost. Finally, its ascertainment of the full methylome enables elucidation of additional biological complexity and inter-tumoural heterogeneity that has hitherto been inaccessible. These findings provide proof-of-concept for clinical adoption of low-pass WGBS, applied using standard WGS technology.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"132"},"PeriodicalIF":6.2,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12186449/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144482820","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
ATRX loss in adult gliomas lacking H3 alterations or IDH mutations, an exceptional situation for exceptional diagnoses: the experience of Sainte-Anne hospital. 缺乏H3改变或IDH突变的成人胶质瘤中ATRX缺失,这是特殊诊断的特殊情况:Sainte-Anne医院的经验。
IF 6.2 2区 医学
Acta Neuropathologica Communications Pub Date : 2025-06-13 DOI: 10.1186/s40478-025-02044-6
Arnault Tauziède-Espariat, Alexandre Roux, Joseph Benzakoun, Paul Kauv, Sanaa Tazi, Alice Métais, Abigail K Suwala, Felix Hinz, Lauren Hasty, Mathilde Filser, Julien Masliah-Planchon, Raphaël Saffroy, Margot Bucau, Johan Pallud, Pascale Varlet
{"title":"ATRX loss in adult gliomas lacking H3 alterations or IDH mutations, an exceptional situation for exceptional diagnoses: the experience of Sainte-Anne hospital.","authors":"Arnault Tauziède-Espariat, Alexandre Roux, Joseph Benzakoun, Paul Kauv, Sanaa Tazi, Alice Métais, Abigail K Suwala, Felix Hinz, Lauren Hasty, Mathilde Filser, Julien Masliah-Planchon, Raphaël Saffroy, Margot Bucau, Johan Pallud, Pascale Varlet","doi":"10.1186/s40478-025-02044-6","DOIUrl":"10.1186/s40478-025-02044-6","url":null,"abstract":"<p><p>ATRX immunostaining constitutes a routinely used biomarker for the practice of neuropathology. The loss of ATRX expression correlating with ATRX gene alterations is implicated in a wide variety of pediatric and adult gliomas, and has been indexed as a desirable or essential diagnostic criterion for four tumor types featured in the latest world health organization classification of central nervous system Tumors. In adult-type diffuse glioma, the loss of ATRX expression is a hallmark of astrocytoma, IDH-mutant. Recently, novel tumor types and alterations have been referenced in the literature. These include the high-grade astrocytoma with piloid features (HGAP), for which no consistent clinicopathological features have been defined, and the presence of other alterations in the Krebs cycle genes (variants of the Fumarate hydratase -FH- gene) found in gliomas resembling astrocytomas, IDH-mutant. Because of this rapidly evolving classification and histomolecular landscape, we retrospectively analyzed adult gliomas diagnosed over a four consecutive year period to identify supratentorial gliomas, lacking H3 alterations or IDH mutations and harboring a loss of ATRX expression, in order to update their diagnoses in terms of histopathology, genetics and epigenetics. Four specimens (from 620 adult gliomas, 0.7%) were reclassified at the end of the molecular workup, as: 1/ one HGAP, 2/ one malignant transformation with a primitive neuronal component of an astrocytoma, IDH-mutant which lost the IDH2 mutation at recurrence, 3/ a glioma, FH-mutant for which the histopathological and epigenetic features were similar to an astrocytoma, IDH-mutant, and 4/ a glioblastoma, IDH-wildtype. To conclude, these exceptional cases extend the spectrum of ATRX loss in gliomas, beyond the astrocytoma, IDH-mutant and the diffuse hemispheric glioma, H3 G34-mutant.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"131"},"PeriodicalIF":6.2,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12164129/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144293140","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Identification of immune subtypes associated with the prognosis in skull base chordoma. 与颅底脊索瘤预后相关的免疫亚型鉴定。
IF 6.2 2区 医学
Acta Neuropathologica Communications Pub Date : 2025-06-13 DOI: 10.1186/s40478-025-02053-5
Yujia Xiong, Mingxuan Li, Guangyi Niu, Tianyi Xu, Chuzhong Li, Tianshun Ma, Tianhao Zhang, Hela Koka, Lili Hao, Yazhuo Zhang, Jiwei Bai, Xiaohong R Yang
{"title":"Identification of immune subtypes associated with the prognosis in skull base chordoma.","authors":"Yujia Xiong, Mingxuan Li, Guangyi Niu, Tianyi Xu, Chuzhong Li, Tianshun Ma, Tianhao Zhang, Hela Koka, Lili Hao, Yazhuo Zhang, Jiwei Bai, Xiaohong R Yang","doi":"10.1186/s40478-025-02053-5","DOIUrl":"10.1186/s40478-025-02053-5","url":null,"abstract":"<p><p>Chordoma is a rare malignant bone tumor that is prone to local recurrence. Recent omics studies suggest that chordoma is a heterogenous disease and the tumor immune microenvironment (TIME) may be associated with chordoma recurrence and patient survival. The aim of this study was to explore the prognostic role of TIME in skull base chordoma. We conducted RNA sequencing of fresh frozen tumors from 77 Chinese skull base chordoma patients and performed unsupervised clustering using immune cell scores estimated by single sample gene set enrichment analysis (ssGSEA) to identify potential immune subtypes. Immunohistochemical (IHC) staining, ESTIMATE, CIBERSORT and xCell were used to validate differences in immune composition between the two immune subtypes. An independent cohort of 261 skull base chordoma patients with long follow-up data was further used to investigate the prognostic associations of immune cells. We identified two immune subtypes (A and B) of skull base chordoma. Compared to tumors in cluster A, tumors in cluster B had higher infiltration of most immune cell populations especially macrophages and T cells. The differences were confirmed by IHC staining of CD68, CD163, and CD3 in a subset of patients (n = 51) with fixed tumor blocks available. Moreover, higher proportions of macrophages (CD68 and CD163) were significantly correlated with shorter PFS (CD68: P < 0.001, CD163: P < 0.001) and OS (CD68: P = 0.04, CD163: P = 0.004) in an independent set of 261 patients with long follow-up data. Our study identified immune subtypes of chordoma that were associated with clinical outcomes and highlighted the potential prognostic value of macrophages. These findings may enhance our understanding of TIME and suggest the importance of macrophages in chordomas.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"130"},"PeriodicalIF":6.2,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12164203/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144293141","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Complement inhibition rapidly blocks lesion extension and facilitates remyelination in neuromyelitis optica. 补体抑制迅速阻断病变扩展,促进视神经脊髓炎的髓鞘再生。
IF 6.2 2区 医学
Acta Neuropathologica Communications Pub Date : 2025-06-12 DOI: 10.1186/s40478-025-02019-7
Katherine S Given, Elizabeth G Acker, Wendy B Macklin, Dan Carlin, Gregory P Owens, Jeffrey L Bennett
{"title":"Complement inhibition rapidly blocks lesion extension and facilitates remyelination in neuromyelitis optica.","authors":"Katherine S Given, Elizabeth G Acker, Wendy B Macklin, Dan Carlin, Gregory P Owens, Jeffrey L Bennett","doi":"10.1186/s40478-025-02019-7","DOIUrl":"10.1186/s40478-025-02019-7","url":null,"abstract":"<p><p>Cumulative disability in neuromyelitis optica spectrum disorder (NMOSD) results from incomplete recovery following inflammatory, demyelinating attacks. Retrospective case studies and current clinical practice indicate that rapid treatment of acute attacks with apheresis limits injury and improves recovery. We evaluated the effects of apheresis and complement inhibition on lesion progression and recovery in a murine ex vivo cerebellar explant model of NMOSD injury. While both strategies reduced lesion formation relative to vehicle treatment, we observed that anti-C5 complement inhibition with eculizumab rapidly halted astrocyte destruction and immediately curtailed lesion extension; whereas an experimental mimic of immunoadsorption (IA), allowed for continued low level astrocyte destruction. During lesion recovery, C5 complement inhibition resulted in a faster rate of oligodendrocyte repopulation and improved myelin repair compared to IA. Complement inhibition may offer multiple benefits for the treatment of acute NMOSD attacks.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"129"},"PeriodicalIF":6.2,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12164113/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144281948","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Beyond the brain: early autonomic dysfunction in Alzheimer's disease. 超越大脑:阿尔茨海默病的早期自主神经功能障碍。
IF 6.2 2区 医学
Acta Neuropathologica Communications Pub Date : 2025-06-10 DOI: 10.1186/s40478-025-02042-8
Carmen Nanclares, Inés Colmena, Alicia Muñoz-Montero, Andrés M Baraibar, Ricardo de Pascual, Aneta Wojnicz, Ana Ruiz-Nuño, Antonio G García, Adrián Gironda-Martínez, Luis Gandía
{"title":"Beyond the brain: early autonomic dysfunction in Alzheimer's disease.","authors":"Carmen Nanclares, Inés Colmena, Alicia Muñoz-Montero, Andrés M Baraibar, Ricardo de Pascual, Aneta Wojnicz, Ana Ruiz-Nuño, Antonio G García, Adrián Gironda-Martínez, Luis Gandía","doi":"10.1186/s40478-025-02042-8","DOIUrl":"10.1186/s40478-025-02042-8","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is classically defined by central hallmarks such as amyloid-beta plaques, tau hyperphosphorylation, and synaptic failure. However, mounting evidence suggests that dysfunction outside the brain, particularly in the peripheral nervous system, may also play a significant role in disease progression. The adrenal medulla-a key regulator of systemic neurotransmission and stress response-has received little attention in this context. In this study, we investigated whether chromaffin cells (CCs) from the triple transgenic AD mouse model (3xTg) exhibit functional alterations that could contribute to peripheral neurochemical imbalance. Using electrophysiology, high-resolution amperometry, and neurotransmitter quantification, we identified early and progressive defects in CC function. Remarkably, even at two months of age-prior to cognitive decline-3xTg CCs showed impaired exocytosis, reduced vesicle release, and slower fusion pore kinetics. These changes were accompanied by diminished sodium (I<sub>Na</sub>), calcium (I<sub>Ca</sub>), and nicotinic (I<sub>ACh</sub>) currents, compromising CC excitability. With age, a shift toward increased potassium (I<sub>K</sub>) currents and enhanced catecholamine secretion may reflect compensatory adaptations aimed at preserving output. These functional deficits were paralleled by structural remodeling of the actin cytoskeleton and systemic neurotransmitter disturbances. Noradrenaline levels increased in both plasma and brain, while dopamine decreased peripherally but paradoxically increased in the prefrontal cortex and hippocampus. Serotonin levels consistently declined across compartments. These imbalances correlated with altered behavior: 3xTg mice displayed increased exploration of exposed areas and heightened behavioral despair, pointing to anxiety- and depression-like phenotypes. Together, our findings identify the adrenal medulla as a previously underrecognized site of early catecholaminergic dysregulation in AD. The observed associations between peripheral CC dysfunction, systemic neurotransmitter imbalance, and behavioral changes point to a potential link between peripheral neuroendocrine alterations and central disease features. These results broaden the current understanding of AD pathophysiology and support the adrenal medulla as a promising candidate for further investigation as a therapeutic target and source of peripheral biomarkers.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"128"},"PeriodicalIF":6.2,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12150586/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144265018","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Single-cell transcriptome sequencing reveals new epithelial-stromal associated mesenchymal-like subsets in recurrent gliomas. 单细胞转录组测序揭示复发性胶质瘤中新的上皮-基质相关间充质样亚群。
IF 6.2 2区 医学
Acta Neuropathologica Communications Pub Date : 2025-06-07 DOI: 10.1186/s40478-025-02036-6
Jinwei Li, Shengrong Long, Yang Zhang, Shuangqi Yu, Hongyu Xu, Rui Liang, Quan Liu, Jinnan Zhang, Xiang Li, Yixin Fu, Tao Xin, Yinyan Wang
{"title":"Single-cell transcriptome sequencing reveals new epithelial-stromal associated mesenchymal-like subsets in recurrent gliomas.","authors":"Jinwei Li, Shengrong Long, Yang Zhang, Shuangqi Yu, Hongyu Xu, Rui Liang, Quan Liu, Jinnan Zhang, Xiang Li, Yixin Fu, Tao Xin, Yinyan Wang","doi":"10.1186/s40478-025-02036-6","DOIUrl":"10.1186/s40478-025-02036-6","url":null,"abstract":"<p><p>Gliomas, particularly glioblastomas, are highly malignant brain tumors with high recurrence rates and poor prognosis. Despite advances in treatment, recurrence remains a major challenge. Epithelial-mesenchymal transition (EMT) plays a key role in tumor invasion and recurrence. This study explores the transcriptional and regulatory mechanisms driving glioma recurrence, focusing on mesenchymal-like (MES-like) subpopulations. Single-nucleus RNA sequencing was performed on 52 IDH wild-type GBM specimens, including 26 primary and 26 recurrent tumors. Spatial transcriptomics data were also incorporated. Tumor subpopulations were identified through gene regulatory network analysis, copy number variation detection, and nonnegative matrix factorization. Functional validation was conducted using gene knockdown experiments, followed by xenograft studies. We discovered novel MES-like subpopulations in recurrent GBM enriched with EMT-related genes like EGR1 and SERPINE1. These subpopulations exhibited increased transcriptional activity and were associated with poor prognosis and invasiveness. Knockdown of SERPINE1 significantly reduced cell proliferation and migration. Spatial transcriptomics showed MES-like cells concentrated at the tumor margins, highlighting their role in invasion and recurrence. MES-like subpopulations, driven by EGR1 and SERPINE1, are critical in GBM. Targeting these regulators could offer new therapeutic strategies to reduce glioma recurrence and improve outcomes.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"127"},"PeriodicalIF":6.2,"publicationDate":"2025-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12145596/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144245662","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Overcoming temozolomide resistance in glioma: recent advances and mechanistic insights. 克服替莫唑胺在胶质瘤中的耐药性:最近的进展和机制见解。
IF 6.2 2区 医学
Acta Neuropathologica Communications Pub Date : 2025-06-05 DOI: 10.1186/s40478-025-02046-4
Hengzeng Li, Yahui Wu, Yue Chen, Jinquan Lv, Chengkang Qu, Tingjie Mei, Yunfan Zheng, Cheng Ye, Feifei Li, Shuo Ge, Anhui Yao, Liyun Jia
{"title":"Overcoming temozolomide resistance in glioma: recent advances and mechanistic insights.","authors":"Hengzeng Li, Yahui Wu, Yue Chen, Jinquan Lv, Chengkang Qu, Tingjie Mei, Yunfan Zheng, Cheng Ye, Feifei Li, Shuo Ge, Anhui Yao, Liyun Jia","doi":"10.1186/s40478-025-02046-4","DOIUrl":"10.1186/s40478-025-02046-4","url":null,"abstract":"<p><p>Temozolomide (TMZ) remains the cornerstone chemotherapy for glioma, yet intrinsic and acquired resistance mechanisms significantly limit its clinical effectiveness. This review summarizes the multifaceted molecular pathways contributing to TMZ resistance, including enhanced DNA repair mechanisms such as O<sup>6</sup>-methylguanine-DNA methyltransferase (MGMT), mismatch repair (MMR), and base excision repair (BER). Additional resistance factors include genetic mutations that affect the drug response, dysregulated non-coding RNAs (miRNAs, lncRNAs, and circRNAs), glioma stem cells (GSCs), cytoprotective autophagy, an immunosuppressive tumor microenvironment (TME), altered signaling pathways, and active drug efflux transporters. Recent advancements to overcome these resistance mechanisms, including enhancing TMZ bioavailability through nanoparticle-based delivery systems and the inhibition of efflux transporters, have been explored. Novel therapeutic approaches that target DNA repair pathways and manipulate autophagy are highlighted. Immunotherapeutic interventions reversing immune suppression and metabolic strategies targeting tumor metabolism offer additional avenues. Emerging therapies such as CRISPR-based gene editing, phytochemical combinations, repurposed drugs, and novel TMZ analogs designed to bypass MGMT-mediated resistance are also discussed. This review highlights current developments and identifies emerging areas, with the goals of enhancing clinical outcomes and prolonging survival for glioma patients.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"126"},"PeriodicalIF":6.2,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12139195/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144223976","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Lipid metabolism disorder promoting retinal structural and functional damage in ApoE-/- mice with age superposition. 脂质代谢紊乱促进ApoE-/-年龄叠加小鼠视网膜结构和功能损伤。
IF 6.2 2区 医学
Acta Neuropathologica Communications Pub Date : 2025-06-04 DOI: 10.1186/s40478-025-02043-7
Rucui Yang, Shaolang Chen, Tsz Kin Ng, Jiajian Liang, Shaofen Huang, Minru Deng, Zhenggen Wu, Yaru Sun, Changzhen Fu, Chi Pui Pang, Qingping Liu, Mingzhi Zhang
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