Acta Neuropathologica Communications最新文献

{"title":"Comparison of plasma ALZpath p-Tau217 with Lilly p-Tau217 and p-Tau181 in a neuropathological cohort.","authors":"Divya Bali, Gemma Salvadó, Thomas G Beach, Geidy E Serrano, Alireza Atri, Eric M Reiman, Andreas Jeromin, Oskar Hansson, Shorena Janelidze","doi":"10.1186/s40478-025-02064-2","DOIUrl":"10.1186/s40478-025-02064-2","url":null,"abstract":"<p><p>There is an urgent need for accurate and validated methods to measure plasma phosphorylated tau (p-Tau) biomarkers in Alzheimer's disease (AD). In this study, we compared the performance of new commercially available plasma p-Tau217 assay developed by ALZpath to other established p-Tau assays in an autopsy-confirmed sample. We included 72 participants from the Arizona Study of Aging and Neurodegenerative Disorders cohort, with antemortem plasma assessments and postmortem neuropathological examination. Plasma p-Tau217 was measured using the single molecule arrays (SIMOA)-based ALZpath immunoassay and plasma p-Tau217 and p-Tau181 were analyzed with mesoscale discovery (MSD)-based immunoassays developed by Lilly Research Laboratories. Plasma biomarkers were compared with densities of post-mortem-assessed amyloid plaques and neurofibrillary changes. Levels of p-Tau217_ALZpath, p-Tau217_Lilly and p-Tau181_Lilly were significantly associated with plaque (partial Spearman ρ = 0.58, ρ = 0.78, ρ = 0.65; p < 0.001) and neurofibrillary (ρ = 0.26, ρ = 0.51, ρ = 0.37; p < 0.05) density scores, adjusting for age, sex, and time of interval between blood sampling and death. All three biomarkers were also significantly associated with plaque density scores (p-Tau217_ALZpath, ρ = 0.53; p-Tau217_Lilly, ρ = 0.73; p-Tau181_Lilly, ρ = 0.59; p < 0.001), when additionally adjusting for neurofibrillary density scores. However, only p-Tau217_Lilly was significantly associated with neurofibrillary density scores (ρ = 0.32, p = 0.022), when adjusting for plaque density scores. The correlations of p-Tau217_ALZpath and p-Tau181_Lilly with plaque density scores were comparable, whereas p-Tau217_Lilly exhibited significantly higher correlations with plaques (p_diff≤0.015) and neurofibrillary changes (p_diff≤0.004) than p-Tau217_ALZpath. While p-Tau217_ALZpath and p-Tau181_Lilly predicted the presence of Alzheimer's disease neuropathological change (ADNC), Braak staging (Braak 0-IV vs. Braak V-VI) and CERAD neuritic plaque classification (low/sparse vs. moderate/frequent) with similar accuracies (area under the curve [AUC]_range, 0.74-0.79), p-Tau217_Lilly AUCs were significantly higher (AUC_range,0.82-0.89, p_diff≤0.024) than the AUCs of p-Tau217_ALZpath. In conclusion, p-Tau217_ALZpath exhibited similar performance as p-Tau181_Lilly but its correlations with core measures of AD pathology were significantly lower in comparison with p-Tau217_Lilly. Future studies are warranted to replicate these findings in larger independent cohorts.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"144"},"PeriodicalIF":6.2,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12207803/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144525832","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}

{"title":"Glial and immune dysregulation in glaucoma independent of retinal ganglion cell loss: a human post-mortem histopathology study.","authors":"Akanksha Salkar, Viswanthram Palanivel, Devaraj Basavarajappa, Mehdi Mirzaei, Angela Schulz, Peng Yan, Vivek Gupta, Stuart Graham, Yuyi You","doi":"10.1186/s40478-025-02066-0","DOIUrl":"10.1186/s40478-025-02066-0","url":null,"abstract":"","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"141"},"PeriodicalIF":6.2,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12205501/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144525930","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}

{"title":"Xenoline-polarized macrophages as an alternative in vitro model of tumor-associated macrophages in glioblastoma.","authors":"Hasan Alrefai, Benjamin Lin, Amr Elkholy, Manoj Kumar, Taylor L Schanel, Kevin J Lee, Patricia H Hicks, Joshua C Anderson, Gao Guo, Eun-Young Erin Ahn, C Ryan Miller, Christopher D Willey","doi":"10.1186/s40478-025-02057-1","DOIUrl":"10.1186/s40478-025-02057-1","url":null,"abstract":"<p><p>Tumor-associated macrophages (TAMs) are the most abundant non-cancerous cell type in glioblastoma (GBM) and heavily influence GBM biology, contributing to tumor progression, therapeutic resistance, immune evasion, and neovascularization. Current in vitro models that utilize IL-4/IL-13 stimulation fail to capture the transcriptional and functional heterogeneity of TAMs observed in vivo. In this study, we utilize a serum-free indirect co-culture model with patient-derived xenolines to polarize primary human macrophages and characterize their molecular and functional phenotypes. We demonstrate that xenoline-polarized macrophages diverge from classical M1/M2 states and instead adopt transcriptional signatures reflective of TAM subsets identified from patients. Notably, macrophages polarized with the radiation-therapy selected xenoline, JX14P-RT, exhibited gene expression patterns enriched for interferon response and hypoxia, mirroring recurrent GBM samples. In contrast, JX14P TAMs showed enrichment in phagocytic gene sets. Functional validation of these phenotypes revealed discrepancies between the transcriptionally predicted and observed phenotypes, emphasizing the importance of integrating phenotypic validation in sequencing studies. Altogether, our findings establish xenoline-polarized macrophages as a useful alternative to traditional models that can be used to study immune-interactions in vitro.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"137"},"PeriodicalIF":6.2,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12205497/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144525934","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}

{"title":"Acquired neuropathology and its associations with key patterns of placental pathology.","authors":"Angela N Viaene, Jasmine Steele, Rebecca L Linn","doi":"10.1186/s40478-025-02065-1","DOIUrl":"10.1186/s40478-025-02065-1","url":null,"abstract":"<p><p>Perinatal brain injury is a major cause of neurodevelopmental disability worldwide. Placental pathology has been implicated as a likely cause of injury to the developing central nervous system (CNS). This study aims to elucidate the associations of multiple placental pathologies and CNS injury, including more subtle brain pathologies associated with adverse neurologic outcomes. Sixty-five subjects that underwent complete post-mortem neuropathologic examination and placental examination were selected for inclusion. Gross images, autopsy reports, and histologic sections from the CNS and placenta underwent blinded reviewed by experts in perinatal neuropathology and placental pathology, respectively. Immunostains useful in highlighting CNS lesions not apparent on routine histologic sections were performed. Placental pathology was classified according to the Amsterdam criteria, and all placental and CNS abnormalities were documented. A previously undescribed association between white matter injury and fetal vascular malperfusion was seen, likely due to improved detection of injury on immunohistochemical stains. Amniotic fluid infection was associated with acute neuronal injury in the cortex and cerebellum as well as subarachnoid hemorrhage. Hippocampal injury had the strongest association with high-grade chronic inflammation, and maternal vascular malperfusion showed higher relative frequencies of acute neuronal injury in the basal ganglia, brainstem, and spinal cord. To our knowledge, this is the first study to standardize placental pathology according to the Amsterdam consensus criteria, separate out injury across multiple CNS regions with independent assessment of these regions, and to utilize immunohistochemistry to improve detection of white matter injury. Different patterns of placental pathology were associated with different types of CNS injury, indicating neuronal injury and white matter injury may be influenced by distinct placental pathologies. Elucidating the placental contributions to these acquired CNS pathologies in stillborns is crucial for understanding long-term adverse neurodevelopmental outcomes associated with perinatal brain injury.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"138"},"PeriodicalIF":6.2,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12205522/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144525830","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}

{"title":"C9orf72 deficiency impairs the autophagic response to aggregated TDP-25 and exacerbates TDP-25-mediated neurodegeneration in vivo.","authors":"Lilian Tsai-Wei Lin, Marc Shenouda, Philip McGoldrick, Agnes Lau, Janice Robertson","doi":"10.1186/s40478-025-02061-5","DOIUrl":"10.1186/s40478-025-02061-5","url":null,"abstract":"<p><p>Cytoplasmic aggregates of the predominantly nuclear TAR DNA-binding protein 43 (TDP-43) are a pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) cases caused by G₄C₂ hexanucleotide repeat expansions in C9orf72 (C9-ALS/FTD). While these repeat expansions are associated with both gain- and loss-of-function mechanisms, the contribution of C9orf72 loss of function to disease pathogenesis remains unclear. C9orf72 has been shown to regulate autophagy, and its deficiency has been shown to exacerbate phenotypes in gain-of-function G₄C₂ models, implicating impaired autophagic clearance in disease pathogenesis. Here, we directly test whether C9orf72 deficiency exacerbates TDP-43 pathology and neurodegeneration in vivo. Using AAV9-vectors to drive neuron-specific expression of pathologically relevant C-terminal species of TDP-43, TDP-35 and TDP-25, we established models of TDP-43 pathology that recapitulate key disease features, including cytoplasmic aggregates, motor and cognitive decline, and neuronal loss. TDP-25 expression in particular produced robust, abnormally phosphorylated, ubiquitinated and p62-labelled cytoplasmic aggregates, modelling TDP-43 pathology in disease. Loss of C9orf72 in TDP-25-expressing mice accelerated the onset of motor deficits, increased neurodegeneration, and impaired the autophagic response to TDP-25 expression. These findings reveal that C9orf72 deficiency disrupts autophagy and exacerbates TDP-25-mediated toxicity in vivo, supporting a contributory role for C9orf72 loss-of-function in driving neurodegeneration in C9-ALS/FTD.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"136"},"PeriodicalIF":6.2,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12205521/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144525831","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}

{"title":"Ultra-low-input cell-free DNA sequencing for tumor detection and characterization in a real-world pediatric brain tumor cohort.","authors":"Tom T Fischer, Kendra K Maaß, Pitithat Puranachot, Markus Mieskolainen, Martin Sill, Paulina S Schad, Stefanie Volz, Fabian Rosing, Tatjana Wedig, Nathalie Schwarz, Agnes M E Finster, Florian Iser, Jochen Meyer, Felix Sahm, Olli Lohi, Ahmed El Damaty, Benedikt Brors, Hannu Haapasalo, Stefan M Pfister, Joonas Haapasalo, Kristian W Pajtler, Kristiina Nordfors","doi":"10.1186/s40478-025-02024-w","DOIUrl":"10.1186/s40478-025-02024-w","url":null,"abstract":"<p><p>Molecular profiling of pediatric central nervous system (CNS) tumors has important clinical utility for guiding diagnostic and therapeutic strategies. Cell-free DNA (cfDNA) from liquid biopsies has been used for minimally invasive tumor profiling and longitudinal disease assessment in adult oncology and pediatric hematology. However, in pediatric neuro-oncology, low cfDNA yields pose a major barrier to translating these assays from bench to bedside. Here, we implemented a low-coverage whole genome sequencing (lcWGS) assay for picogram-level cfDNA inputs and applied it to liquid biopsies from a sizeable, population-based, cross-entity pediatric CNS tumor cohort (n = 56 patients). Applying this protocol, cfDNA whole genome profiles were successfully acquired from all liquid biopsy samples (n = 61/61 serum, n = 56/56 CSF, 100%). Based on copy number variations (CNVs), circulating-tumor DNA (ctDNA) was detected in 2/61 serum (3%) and in 25/56 CSF (45%) samples across various brain tumor entities. The integration of cfDNA results with clinical data demonstrated the utility of CSF lcWGS as a biomarker assay at diagnosis to distinguish cancerous from non-cancerous pineal region lesions (n = 6 patients). Additionally, serial CSF assessment in n = 9 patients (n = 29 CSF samples) enabled minimally invasive disease monitoring, with the added value of molecular profile availability in n = 4/6 (67%) patients at relapse. Proof-of-concept data show the feasibility of serial CSF lcWGS to reveal tumor evolution, tumor heterogeneity and potential therapeutic vulnerabilities in a case of medulloblastoma and germ cell tumor. Our study underscores the clinical utility of a robust lcWGS-based liquid biopsy assay optimized for low-input samples. We identify use-cases for implementing liquid biopsies in the clinical management of pediatric CNS tumor patients and provide a strong rationale for integration into future trials.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"134"},"PeriodicalIF":6.2,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12205504/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144511396","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}

{"title":"Co-occurrence of myositis and neuropathy after anti-CD30 therapy in a late-adolescent Hodgkin lymphoma patient.","authors":"Adela Della Marina, Lydia Rink, Andreas Hentschel, Michael M Schündeln, Christopher Nelke, Heike Kölbel, Calvin Tucht, Vera Dobelmann, Tobias Ruck, Tim Hagenacker, Teresinha Evangelista, Ulrike Schara-Schmidt, Andreas Roos","doi":"10.1186/s40478-025-02056-2","DOIUrl":"10.1186/s40478-025-02056-2","url":null,"abstract":"<p><strong>Objective: </strong>Immune-related adverse events (irAEs) are recognized in oncology, particularly with immune checkpoint inhibitors and other targeted therapies. Brentuximab Vedotin (BV), is an anti-CD30 antibody-drug conjugate- its association with immune-mediated myositis remains unexplored. We report a case of an adolescent with Hodgkin lymphoma (HL) who developed neuropathy and myositis following BV therapy.</p><p><strong>Materials & methods: </strong>The diagnostic work-up included MRI as well as microscopic analyses (histology, electron microscopy, and immunostainings including CD30 and MxA) of a gastrocnemius muscle biopsy. Proteomic analysis was also performed on the same biopsy, and paradigmatic protein dysregulations were validated through immunostaining. Serum NCAM1 levels were measured using ELISA.</p><p><strong>Results: </strong>The patient, diagnosed with HL at 15 years, developed neuropathy after Vincristine treatment and was switched to BV. During BV therapy, she experienced progressive muscle weakness and foot drop, leading to discontinuation. MRI confirmed myositis, and biopsy revealed neurogenic and inflammatory changes with complement deposition and mitochondrial dysfunction. Proteomics showed upregulation of inflammatory relevant proteins, with HPRT1 (749.43-fold) being the most increased one. Intravenous immunoglobulin (IVIG) therapy improved muscle strength.</p><p><strong>Discussion: </strong>Myositis following BV therapy has not been reported. Findings suggest an immune-mediated mechanism with B-cell involvement. Given the response to IVIG, B-cell-directed therapies may be beneficial. This case identifies BV-induced myositis as a novel irAE.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"140"},"PeriodicalIF":6.2,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12205510/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144525833","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}

{"title":"Transcription factor-based classification of pituitary adenomas / PitNETs: a comparative analysis and clinical implications across WHO 2004, 2017 and 2022 in 921 cases.","authors":"Isabella Nasi-Kordhishti, Mirko Hladik, Kosmas Kandilaris, Felix Behling, Jürgen Honegger, Jens Schittenhelm","doi":"10.1186/s40478-025-02050-8","DOIUrl":"10.1186/s40478-025-02050-8","url":null,"abstract":"<p><p>The WHO classifications of 2017 and 2022 recommend the use of pituitary transcription factors PIT-1, T-PIT and SF-1 as well as GATA3 and ERα for histopathological diagnosis. The aim of this study is to demonstrate their diagnostic impact in a large retrospective cohort. 921 PitNETs/PAs diagnosed in our department between October 2004 and April 2018 were retrospectively reassessed according to the WHO classifications 2017 and 2022. The original classification (WHO 2004) and the clinical data were retrieved from the patient records. Hormone-immunonegative null cell adenomas represented the largest subgroup (397 of 921) in the WHO 2004 classification. Of these, 377 were reclassified as gonadotroph PitNETs/PAs, and 14 were assigned to a non-gonadotroph hormone-producing cell line. Only 6 cases remained null cell tumors. 27 of 35 plurihormonal adenomas were assigned to a specific cell line in the 2017 and 2022 WHO classifications. Of 489 adenomas formerly classified as expressing of 1 or 2 hormones, the histopathological diagnosis was confirmed in 459 cases with the use of TP. Of the remaining 30 cases, 12 cases with positive immunostaining of 2 hormones could be assigned to a single cell line, and 18 cases changed their lineage. The correct correlation with clinical data significantly improved from 75.4% (WHO 2004) to 96.2% (WHO 2017 and 2022). Corticotroph PitNETs showed the highest risk for recurrence (21.9%) and progression (55.8%). The new classification enables more accurate (sub)classification and significantly improves clinicopathological correlation. In individual cases, it is essential to consider the reclassification to predict the clinical prognosis and to schedule the follow-up accordingly.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"135"},"PeriodicalIF":6.2,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12205515/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144511395","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}

{"title":"Impaired splicing machinery in craniopharyngiomas unveils PRPF8 and RAVER1 as novel biomarkers and therapeutic targets.","authors":"Antonio C Fuentes-Fayos, Miguel E G-García, Teresa Sánchez-Medianero, John Apps, Álvaro Flores-Martínez, Ana S De la Rosa-Herencia, Ignacio Gil-Duque, Georg Otto, Eva Venegas-Moreno, Eugenio Cárdenas Ruiz-Valdepeñas, Aura D Herrera-Martínez, Juan Solivera, Manuel D Gahete, David A Cano, Rosa Ortega, Alfonso Soto-Moreno, María A Gálvez-Moreno, Juan Pedro Martínez-Barberá, Raúl M Luque","doi":"10.1186/s40478-025-02040-w","DOIUrl":"10.1186/s40478-025-02040-w","url":null,"abstract":"<p><p>Craniopharyngiomas are rare benign pathologies but clinically challenging tumours because of their intimate relationship with critical brain structures, leading to severe endocrine-deficiencies/comorbidities. Therefore, identifying alternative prognostic/therapeutic tools is crucial. Although dysregulated splicing is a molecular feature that characterizes almost all tumour/cancer types, the dysregulation of the components belonging to the molecular machinery controlling the splicing-process (spliceosome) remains unknown in craniopharyngiomas. Here, we uncover a profound dysregulation in the expression of relevant spliceosome-components and splicing-factors in craniopharyngiomas versus control non-tumour tissues, identifying PRPF8 and RAVER1 as key tumour suppressor factors associated with relevant oncogenic processes. Moreover, we demonstrate that the spliceosome activity inhibition using pladienolide-B in primary patient´s derived cell-cultures might serve as a potential therapeutic tool worth to be explored in humans. Altogether, our results demonstrate a drastic and clinically relevant spliceosome-associated molecular dysregulation in craniopharyngiomas, which could serve as a potential source of novel diagnostic/prognostic biomarkers and therapeutic targets.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"142"},"PeriodicalIF":6.2,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12205502/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144525932","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}

{"title":"Identifying and exploiting combinatorial synthetic lethality by characterizing adaptive kinome rewiring of EGFRvIII-driven glioblastoma.","authors":"Benjamin Lin, Abigail K Shelton, Erin Smithberger, Julia Ziebro, Kasey R Skinner, Ryan E Bash, Richard Kirkman, Allie Stamper, Madison Butler, Alex Flores, Steven P Angus, Michael P East, Timothy F Cloughesy, David A Nathanson, Michael E Berens, Jann N Sarkaria, Zev A Binder, Donald M O'Rourke, Timothy C Howton, Brittany N Lasseigne, Christopher D Willey, Gary L Johnson, Anita B Hjelmeland, Frank B Furnari, C Ryan Miller","doi":"10.1186/s40478-025-02068-y","DOIUrl":"10.1186/s40478-025-02068-y","url":null,"abstract":"<p><p>GBM is an aggressive primary malignant brain tumor that has a poor prognosis. Molecular characterization of GBM has shown that EGFR mutations are present in over 50% of tumors. However, EGFR inhibitors have not shown clinical efficacy in contrast to other EGFR-driven neoplasms due to the unique EGFR biology found in GBM. Upfront combinatorial therapy featuring EGFR tyrosine kinase inhibitors (TKI) may overcome these challenges. To identify combinatorial drug targets within the kinome, we temporally characterized drug-induced kinome rewiring in isogenic, genetically engineered Cdkn2a-deleted mouse astrocytes expressing human EGFRvIII. We utilize RNA sequencing and multiplex inhibitor beads, coupled with mass spectrometry, to demonstrate that kinome rewiring exhibits both shared and unique kinases after acquired resistance develops to EGFR TKI, despite using models with a common genetic background. Additionally, we noted that kinases altered in the acute setting are distinct from those in acquired resistance. By identifying kinome vulnerabilities throughout the acute, dynamic drug response process, we generated a kinase signature associated with EGFR inhibition. Further molecular interrogation of signature genes revealed that drug treatment induces an unexpected increase in Cdk6 protein, but not mRNA, despite live cell imaging and transcriptomic evidence indicating decreased proliferation. Survival experiments with orthotopic allografts show that upfront combination inhibition of Cdk6, using abemaciclib, and EGFR, using neratinib, significantly prolonged median survival compared to neratinib alone. Our findings suggest that identifying and inhibiting targets with synthetic lethality in the upfront combinatorial setting is a viable approach for precision oncology and may help provide an avenue to overcome the resistance mechanisms that contributed to the failures of EGFR as a molecular target in GBM.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"143"},"PeriodicalIF":6.2,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12205505/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144525931","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}