A clinically applicable integrative molecular classification of meningiomas.

Meningiomas are the most common primary intracranial tumour in adults1. Patients with symptoms are generally treated with surgery as there are no effective medical therapies. The World Health Organization histopathological grade of the tumour and the extent of resection at surgery (Simpson grade) are associated with the recurrence of disease; however, they do not accurately reflect the clinical behaviour of all meningiomas2. Molecular classifications of meningioma that reliably reflect tumour behaviour and inform on therapies are required. Here we introduce four consensus molecular groups of meningioma by combining DNA somatic copy-number aberrations, DNA somatic point mutations, DNA methylation and messenger RNA abundance in a unified analysis. These molecular groups more accurately predicted clinical outcomes compared with existing classification schemes. Each molecular group showed distinctive and prototypical biology (immunogenic, benign NF2 wild-type, hypermetabolic and proliferative) that informed therapeutic options. Proteogenomic characterization reinforced the robustness of the newly defined molecular groups and uncovered highly abundant and group-specific protein targets that we validated using immunohistochemistry. Single-cell RNA sequencing revealed inter-individual variations in meningioma as well as variations in intrinsic expression programs in neoplastic cells that mirrored the biology of the molecular groups identified.

NF2 regulates IP3R-mediated Ca2+ signal and apoptosis in meningiomas.

Meningiomas are the most common primary intracranial tumors and account for nearly 30% of all nervous system tumors. Approximately half of meningioma patients exhibit neurofibromin 2 (NF2) gene inactivation. Here, NF2 was shown to interact with the endoplasmic reticulum (ER) calcium (Ca2+) channel inositol 1,4,5-trisphosphate receptor 1 (IP3R1) in IOMM-Lee, a high-grade malignant meningioma cell line, and the F1 subdomain of NF2 plays a critical role in this interaction. Functional assays indicated that NF2 promotes the phosphorylation of IP3R (Ser 1756) and IP3R-mediated endoplasmic reticulum (ER) Ca2+ release by binding to IP3R1, which results in Ca2+-dependent apoptosis. Knockout of NF2 decreased Ca2+ release and promoted resistance to apoptosis, which was rescued by wild-type NF2 overexpression but not by F1 subdomain deletion truncation overexpression. The effects of NF2 defects on the development of tumors were further studied in mouse models. The decreased expression level of NF2 caused by NF2 gene knockout or mutation affects the activity of the IP3R channel, which reduces Ca2+-dependent apoptosis, thereby promoting the development of tumors. We elucidated the interaction patterns of NF2 and IP3R1, revealed the molecular mechanism through which NF2 regulates IP3R1-mediated Ca2+ release, and elucidated the new pathogenic mechanism of meningioma-related NF2 variants. Our study broadens the current understanding of the biological function of NF2 and provides ideas for drug screening of NF2-associated meningioma.

α-Mannosylated HLA-II glycopeptide antigens dominate the immunopeptidome of immortalised cells and tumour tissues.

Immunopeptides are cell surface-located protein fragments that aid our immune system to recognise and respond to pathogenic insult and malignant transformation. In this two-part communication, we firstly summarise and reflect on our recent discovery documenting that MHC-II-bound immunopeptides from immortalised cell lines prevalently carry N-glycans that differ from the cellular glycoproteome (Goodson, Front Immunol, 2023). These findings are important as immunopeptide glycosylation remains poorly understood in immunosurveillance. The study also opened up new technical and biological questions that we address in the second part of this communication. Our study highlighted that the performance of the search engines used to detect glycosylated immunopeptides from LC-MS/MS data remains untested and, importantly, that little biochemical in vivo evidence is available to document the nature of glycopeptide antigens in tumour tissues. To this end, we compared the N-glycosylated MHC-II-bound immunopeptides that were reported from tumour tissues of 14 meningioma patients in the MSFragger-HLA-Glyco database (Bedran, Nat Commun, 2023) to those we identified with the commercial Byonic software. Encouragingly, the search engines produced similar outputs supporting that N-glycosylated MHC-II-bound immunopeptides are prevalent in meningioma tumour tissues. Consistent also with in vitro findings, the tissue-derived MHC-II-bound immunopeptides were found to predominantly carry hyper-processed (paucimannosidic- and chitobiose core-type) and hypo-processed (oligomannosidic-type) N-glycans that varied in prevalence and distribution between patients. Taken together, evidence is emerging suggesting that α-mannosidic glycoepitopes abundantly decorate MHC-II-bound immunopeptides presented in both immortalised cells and tumour tissues warranting further research into their functional roles in immunosurveillance.

Drug target therapy and emerging clinical relevance of exosomes in meningeal tumors.

Meningioma is the most common central nervous system (CNS) tumor. In recent decades, several efforts have been made to eradicate this disease. Surgery and radiotherapy remain the standard treatment options for these tumors. Drug therapy comes to play its role when both surgery and radiotherapy fail to treat the tumor. This mostly happens when the tumors are close to vital brain structures and are nonbenign. Although a wide variety of chemotherapeutic drugs and molecular targeted drugs such as tyrosine kinase inhibitors, alkylating agents, endocrine drugs, interferon, and targeted molecular pathway inhibitors have been studied, the roles of numerous drugs remain unexplored. Recent interest is growing toward studying and engineering exosomes for the treatment of different types of cancer including meningioma. The latest studies have shown the involvement of exosomes in the theragnostic of various cancers such as the lung and pancreas in the form of biomarkers, drug delivery vehicles, and vaccines. Proper attention to this new emerging technology can be a boon in finding the consistent treatment of meningioma.

Application of 5T glutamate chemical exchange saturation transfer imaging in brain tumors: preliminary results.

PURPOSE: Glutamate chemical exchange saturation transfer (GluCEST) is a non-invasive CEST imaging technique for detecting glutamate levels in tissues. We aimed to investigate the reproducibility of the 5T GluCEST technique in healthy volunteers and preliminarily explore its potential clinical application in patients with brain tumors. METHODS: Ten volunteers (4 males, mean age 29 years) underwent three 5T GluCEST imaging scans. The reproducibility of the three imaging GluCEST measurements was assessed using one-way repeated measures analysis of variance (ANOVA), generalized estimating equations, and linear mixed models. Twenty-eight patients with brain tumors (10 males, mean age 54 years) underwent a single GluCEST scan preoperatively, and t-tests were used to compare the differences in GluCEST values between different brain tumors. In addition, the diagnostic accuracy of GluCEST values in differentiating brain tumors was assessed using the receiver work characteristics (ROC) curve. RESULTS: The coefficients of variation of GluCEST values in healthy volunteers were less than 5% for intra-day, inter-day, and within-subjects and less than 10% for between-subjects. High-grade gliomas (HGG) had higher GluCEST values compared to low-grade gliomas (LGG) (P < 0.001). In addition, cerebellopontine angle (CPA) meningiomas had higher GluCEST values than acoustic neuromas (P < 0.001). The area under the curve (AUC) of the GluCEST value for differentiating CPA meningioma from acoustic neuroma was 0.93. CONCLUSION: 5T GluCEST images are highly reproducible in healthy brains. In addition, the 5T GluCEST technique has potential clinical applications in differentiating LGG from HGG and CPA meningiomas from acoustic neuromas.

Inhibition of BMP signaling pathway induced senescence and calcification in anaplastic meningioma.

PURPOSE: Meningiomas are the most common type of brain tumors and are generally benign, but malignant atypical meningiomas and anaplastic meningiomas frequently recur with poor prognosis. The metabolism of meningiomas is little known, so few effective treatment options other than surgery and radiation are available, and the targets for treatment of recurrence are not well defined. The Aim of this paper is to find the therapeutic target. METHODS: The effects of bone morphogenetic protein (BMP) signal inhibitor (K02288) and upstream regulator Gremlin2 (GREM2) on meningioma's growth and senescence were examined. In brief, we examined as follows: 1) Proliferation assay by inhibiting BMP signaling. 2) Comprehensive analysis of forced expression GREM2.3) Correlation between GREM2 mRNA expression and proliferation marker in 87 of our clinical samples. 4) Enrichment analysis between GREM2 high/low expressed groups using RNA-seq data (42 cases) from the public database GREIN. 5) Changes in metabolites and senescence markers associated with BMP signal suppression. RESULTS: Inhibitors of BMP receptor (BMPR1A) and forced expression of GREM2 shifted tryptophan metabolism from kynurenine/quinolinic acid production to serotonin production in malignant meningiomas, reduced NAD + /NADH production, decreased gene cluster expression involved in oxidative phosphorylation, and caused decrease in ATP. Finally, malignant meningiomas underwent cellular senescence, decreased proliferation, and eventually formed psammoma bodies. Reanalyzed RNA-seq data of clinical samples obtained from GREIN showed that increased expression of GREM2 decreased the expression of genes involved in oxidative phosphorylation, similar to our experimental results. CONCLUSIONS: The GREM2-BMPR1A-tryptophan metabolic pathway in meningiomas is a potential new therapeutic target.

Hsa_circ_0004872 mitigates proliferation, metastasis and immune escape of meningioma cells by suppressing PD-L1.

Meningioma is a prevalent intracranial malignancy known for its aggressive growth. Circular RNAs (circRNAs) play a crucial role in the development of various cancers. However, their involvement in meningioma remains understudied. This study aimed to investigate the function and underlying mechanism of hsa_circ_0004872 in meningioma. The molecular expression of hsa_circ_0004872, PD-L1 and EIF4A3 was identified by RT-qPCR and/or western blot assays. Cell viability, migration, and invasion were assessed through CCK-8 and Transwell assays, respectively. Cytotoxicity was determined using an LDH assay, and cell apoptosis was monitored by flow cytometry. The RNA and protein interactions were assessed through RNA-protein immunoprecipitation (RIP) and RNA pull down analyses. Our findings revealed that hsa_circ_0004872 expression was significantly downregulated in both meningioma tissue samples and cells. Overexpression of hsa_circ_0004872 inhibited the proliferation, metastasis, and immune escape of meningioma cells, as well as enhanced the cytotoxicity of CD8+ T cells by suppressing PD-L1. Furthermore, hsa_circ_0004872 directly interacted with EIF4A3, leading to the degradation of PD-L1 mRNA. Finally, inhibiting EIF4A3 improved the proliferation, metastasis, and immune escape of meningioma cells, as well as the cytotoxicity of CD8+ T cells. Our study demonstrated that hsa_circ_0004872 mitigated the proliferation, metastasis,and immune escape of meningioma cells by targeting the EIF4A3/PD-L1 axis. These findings suggested that hsa_circ_0004872 and EIF4A3 might serve as promising biological markers and therapeutic targets for meningioma treatment.

The value of whole tumor apparent diffusion coefficient histogram parameters in predicting meningiomas progesterone receptor expression.

This letter provides a critical assessment of a previous study on the utility of whole tumor apparent diffusion coefficient (ADC) histogram characteristics in predicting meningioma progesterone receptor expression. While acknowledging the benefits of employing classical diffusion-weighted imaging (DWI) for non-invasive tumor evaluation, it also emphasizes significant drawbacks. Advanced imaging techniques such as diffusion tensor imaging (DTI) and diffusion kurtosis imaging (DKI) were not used in the study, which could have provided a more comprehensive understanding of tumor microstructure and heterogeneity. Furthermore, the inclusion of necrotic and cystic areas in ADC analysis may distort results due to their different diffusion properties. While focusing on first-order ADC histogram characteristics is useful, it ignores the potential insights gained from higher-order features and texture analysis. These limitations indicate that future research should combine improved imaging modalities with thorough analytical methodologies to increase the predictive value of imaging biomarkers for meningioma features and progesterone receptor expression.

The value of whole tumor apparent diffusion coefficient histogram parameters in predicting meningiomas progesterone receptor expression.

PURPOSE: This study investigated the value of whole tumor apparent diffusion coefficient (ADC) histogram parameters and magnetic resonance imaging (MRI) semantic features in predicting meningioma progesterone receptor (PR) expression. MATERIALS AND METHODS: The imaging, pathological, and clinical data of 53 patients with PR-negative meningiomas and 52 patients with PR-positive meningiomas were retrospectively reviewed. The whole tumor was outlined using Firevoxel software, and the ADC histogram parameters were calculated. The differences in ADC histogram parameters and MRI semantic features were compared between the two groups. The predictive values of parameters for PR expression were assessed using receiver operating characteristic curves. The correlation between whole-tumor ADC histogram parameters and PR expression in meningiomas was also analyzed. RESULTS: Grading was able to predict the PR expression in meningiomas (p = 0.012), though the semantic features of MRI were not (all p > 0.05). The mean, Perc.01, Perc.05, Perc.10, Perc.25, and Perc.50 histogram parameters were able to predict meningioma PR expression (all p < 0.05). The predictive performance of the combined histogram parameters improved, and the combination of grade and histogram parameters provided the optimal predictive value, with an area under the curve of 0.849 (95%CI: 0.766-0.911) and sensitivity, specificity, ACC, PPV, and NPV of 73.08%, 81.13%, 77.14%, 79.20%, and 75.40%, respectively. The mean, Perc.01, Perc.05, Perc.10, Perc.25, and Perc.50 histogram parameters were positively correlated with PR expression (all p < 0.05). CONCLUSION: Whole tumor ADC histogram parameters have additional clinical value in predicting PR expression in meningiomas.

A Comprehensive Study of Meningioma Biomineralization: Morphological, Crystallographic, and Immunohistochemical Aspects.

Biomineralization of brain tissues occurs both in normal and pathological conditions. Dura mater biomineralization is widespread and occurs in 1-72% of cases, depending on the patient's age and research method. The amount of biomineral deposits under the conditions of tumor growth in the meninges only increases, reaching 100% in the case of psammomatous meningiomas. Since calcifications are often found in the meninges, the problem of differential diagnosis with calcified meningiomas arises. A total of 30 samples of meningiomas with signs of biomineralization-dense structure, characteristic crunch, psammoma bodies (group I) and 30 samples of meningiomas without any signs of biomineralization were examined as controls (group II). To detect pathological biomineralization, the meningioma tissue was studied using the methods of macroscopic description, histology, histochemistry, and immunohistochemistry, scanning electron microscopy with microanalysis, and transmission electron microscopy. A significantly higher level of caspase3 and features of the expression of osteoblastic markers (a lower level of OPG expression and a higher level of the presence of RANKL in group I, the absence of fluctuations in the expression of SPARC) may indicate a dystrophic type of development of biomineral deposits in meningiomas.

Effect of Different Glucose Levels and Glycation on Meningioma Cell Migration and Invasion.

Meningiomas are predominantly benign tumors, but there are also malignant forms that are associated with a poor prognosis. Like almost all tumors, meningiomas metabolize glucose as part of aerobic glycolysis (Warburg effect) for energy supply, so there are attempts to influence the prognosis of tumor diseases using a glucose-reduced diet. This altered metabolism leads to so called hallmarks of cancer, such as glycation and glycosylation. In this study, we investigated the influence of low (3 mM), normal (5.5 mM) and high glucose (15 mM) on a malignant meningioma cell line (IOMM-Lee, WHO grade 3). In addition, the influence of methylglyoxal, a by-product of glycolysis and a precursor for glycation, was investigated. Impedance-based methods (ECIS and RTCA) were used to study migration and invasion, and immunoblotting was used to analyze the expression of proteins relevant to these processes, such as focal adhesion kinase (FAK), merlin or integrin ß1. We were able to show that low glucose reduced the invasive potential of the cells, which was associated with a reduced amount of sialic acid. Under high glucose, barrier function was impaired and adhesion decreased, which correlated with a decreased expression of FAK.

[Methylthioadenosine phosphorylase and p16 as surrogate diagnostic markers for CDKN2A homozygous deletion in brain tumors].

Objective: To examine whether immunohistochemistry of methylthioadenosine phosphorylase (MTAP) and p16 could be used to predict the CDKN2A status in various brain tumors. Methods: A total of 118 cases of IDH-mutant astrocytomas, 16 IDH-wildtype glioblastoma, 17 polymorphic xanthoastrocytoma (PXA) and 20 meningiomas diagnosed at Xuanwu Hospital, Capital Medical University, Beijing, China from November 2017 to October 2023 were collected and analyzed. The CDKN2A status was detected by using fluorescence in situ hybridization or next-generation sequencing. Expression of MTAP and p16 proteins was detected with immunohistochemistry. The association of loss of MTAP/p16 expression with CDKN2A homozygous/heterozygous deletion was examined. Results: Among the 118 cases of IDH-mutant astrocytoma, 13 cases showed homozygous deletion of CDKN2A. All of them had no expression of MTAP while 9 cases had no expression of p16. Among the 16 cases of IDH wild-type glioblastoma, 6 cases showed homozygous deletion of CDKN2A. All 6 cases had no expression of MTAP, while 3 of these cases had no expression of p16 expression. Among the 17 PXA cases, 4 cases showed homozygous deletion of CDKN2A, and the expression of MTAP and p16 was also absent in these 4 cases. Among the 20 cases of meningiomas, 4 cases showed homozygous deletion of CDKN2A. Their expression of MTAP and p16 was also absent. Among the four types of brain tumors, MTAP was significantly correlated with CDKN2A homozygous deletion (P<0.05), with a sensitivity of 100%. However, it was only significantly correlated with the loss of heterozygosity (LOH) of CDKN2A in astrocytomas (P<0.001). P16 was associated with CDKN2A homozygous deletion in IDH-mutant astrocytoma and PXA (P<0.001), but not with the LOH of CDKN2A. Its sensitivity and specificity were lower than that of MTAP. Conclusions: MTAP could serve as a predictive surrogate for CDKN2A homozygous deletion in adult IDH-mutant astrocytoma, PXA, adult IDH-wildtype glioblastoma and meningioma. However, p16 could only be used in the first two tumor types, and its specificity and sensitivity are lower than that of MTAP.

Investigation of the status of immune checkpoint molecules (PD-L1 and PD-1) in meningiomas by immunohistochemistry.

Background/aim: Meningiomas are the most common primary brain tumors of the central nervous system. Immunotherapy is a promising treatment method applied in many types of cancer. There is no standard and effective medical treatment to reduce recurrence and mortality in cases of incomplete resection of meningiomas and in high-grade cases. In order to investigate medical treatments in addition to surgery and radiotherapy, in this study, the status of immune checkpoint molecules (PD-L1/PD-1), which are the target of immunotherapy, in meningiomas was investigated. Materials and methods: Four hundred two cases of meningioma diagnosed between 2007 and 2020 at our institution were used. New blocks were prepared from the appropriate blocks of the cases using the tissue microarray method. Sections obtained from these blocks were immunohistochemically stained with PD-1 and PD-L1 antibodies. Obtained data were interpreted with statistical analysis. Results: Expression of PD-L1 was observed in 28.4% of meningiomas. Staining rates are higher in high-grade tumors. The staining rate of PD-L1 in the tumor increased significantly with pattern loss. PD-L1 expression in immune cells is 19.9%. Immune cell expression and the number of expressing immune cells correlate with spontaneous necrosis. Immune cell expression and the number of expressing immune cells are increased in high-grade meningiomas. PD-1 expression in immune cells is 9.0%, and this correlates with brain invasion. Conclusions: With these data, it was observed that the expression of immune checkpoint molecules PD-L1 and PD-1 increased especially in high-grade meningiomas. It may be the subject of research that these molecules may be targets of immunotherapy in the treatment of meningiomas.

The usefulness of [68 Ga]Ga-DOTA-JR11 PET/CT in patients with meningioma: comparison with MRI.

PURPOSE: Clinical studies of PET imaging using SSTR2 agonists have demonstrated high accuracy and correlation with SSTR2 expression in meningiomas. However, the usefulness of the SSTR2 antagonist with [68 Ga]Ga-DOTA-JR11 is uncertain. To evaluate the diagnostic performance of [68 Ga]Ga-DOTA-JR11 PET/CT and to clarify tumor characteristics in patients with suspected meningiomas. MATERIALS AND METHODS: Patients with suspected de novo or recurrent meningioma in complex locations or atypical images were enrolled from August 2021 to October 2022 in prospective study. All patients underwent contrast-enhanced MRI (CE-MRI), [68 Ga]Ga-DOTA-JR11 PET/CT, and histopathological evaluation. Tumor uptake of [68 Ga]Ga-DOTA-JR11 was measured by SUVmax and tumor-endocranium ratio (TBR). Diagnostic performance was compared between PET and MRI. RESULTS: Of 36 (50.0 ± 13.0 years of age, 20 women) patients, 32 were histopathologically confirmed meningiomas and four with other tumors. [68 Ga]Ga-DOTA-JR11 uptake was significantly higher in meningioma patients than in those with other tumors (SUVmax: 13.6 ± 7.7 vs. 5.2 ± 3.0, P < 0.001; TBR: 64.2 ± 27.7 vs. 25.0 ± 18.9, P = 0.001). [68 Ga]Ga-DOTA-JR11 PET/CT detected 31 meningiomas, while CE-MRI detected 17 meningiomas of 25 initial diagnosis and 11 recurrent tumors; [68 Ga]Ga-DOTA-JR11 PET had an incremental diagnostic value of 24% (6/25) over MRI in the group of initial diagnosis. There was no statistically significant difference in diagnostic efficacy between PET and MRI (P = 0.45) for all 36 patients. In skull base meningiomas, PET provided a more definitive diagnosis of pituitary involvement (in 12, not in12), compared to MRI (in eight, possible in six, possible not in six, not in four). PET revealed bone involvement in all 14 patients proven by pathology, while MRI identified only 11. CONCLUSIONS: [68 Ga]Ga-DOTA-JR11 PET/CT provided high image quality and presented an ideal diagnostic performance in detecting meningioma and evaluating the involvement of the pituitary and bone. The study provides valuable evidence for the use of [68 Ga]Ga-DOTA-JR11 PET/CT as a complementary imaging modality to CE-MRI in the evaluation of meningiomas.

Innovative treatments for meningiomas.

Multi-recurrent high-grade meningiomas remain an unmet medical need in neuro-oncology when iterative surgeries and radiation therapy sessions fail to control tumor growth. Nevertheless, the last 10years have been marked by multiple advances in the comprehension of meningioma tumorigenesis via the discovery of new driver mutations, the identification of activated intracellular signaling pathways, and DNA methylation analyses, providing multiple potential therapeutic targets. Today, Anti-VEGF and mTOR inhibitors are the most used and probably the most active drugs in aggressive meningiomas. Peptide radioactive radiation therapy aims to target SSTR2A receptors, which are strongly expressed in meningiomas, but have an insufficient effect in most aggressive meningiomas, requiring the development of new techniques to increase the dose applied to the tumor. Based on the multiple potential intracellular targets, multiple targeted therapy clinical trials targeting Pi3K-Akt-mTOR and MAP kinase pathways as well as cell cycle and particularly, cyclin D4-6 are ongoing. Recently discovered driver mutations, SMO, Akt, and PI3KCA, offer new targets but are mostly observed in benign meningiomas, limiting their clinical relevance mainly to rare aggressive skull base meningiomas. Therefore, NF2 mutation remains the most frequent mutation and main challenging target in high-grade meningioma. Recently, inhibitors of focal adhesion kinase (FAK), which is involved in tumor cell adhesion, were tested in a phase 2 clinical trial with interesting but insufficient activity. The Hippo pathway was demonstrated to interact with NF2/Merlin and could be a promising target in NF2-mutated meningiomas with ongoing multiple preclinical studies and a phase 1 clinical trial. Recent advances in immune landscape comprehension led to the proposal of the use of immunotherapy in meningiomas. Except in rare cases of MSH2/6 mutation or high tumor mass burden, the activity of PD-1 inhibitors remains limited; however, its combination with various radiation therapy modalities is particularly promising. On the whole, therapeutic management of high-grade meningiomas is still challenging even with multiple promising therapeutic targets and innovations.

mTOR kinase inhibition disrupts neuregulin 1-ERBB3 autocrine signaling and sensitizes NF2-deficient meningioma cellular models to IGF1R inhibition.

Meningiomas (MNs), arising from the arachnoid/meningeal layer, are nonresponsive to chemotherapies, with ∼50% showing loss of the Neurofibromatosis 2 (NF2) tumor suppressor gene. Previously, we established NF2 loss activates mechanistic target of rapamycin complex 1 (mTORC1) and mechanistic target of rapamycin complex 2 (mTORC2) signaling, leading to clinical trials for NF2 and MN. Recently our omics studies identified activated ephrin (EPH) receptor and Src family kinases upon NF2 loss. Here, we report increased expression of several ligands in NF2-null human arachnoidal cells (ACs) and the MN cell line Ben-Men-1, particularly neuregulin-1/heregulin (NRG1), and confirm increased NRG1 secretion and activation of V-ERB-B avian erythroblastic leukemia viral oncogene homolog 3 (ERBB3) receptor kinase. Conditioned-medium from NF2-null ACs or exogenous NRG1 stimulated ERBB3, EPHA2, and mTORC1/2 signaling, suggesting pathway crosstalk. NF2-null cells treated with an ERBB3-neutralizing antibody partially downregulated mTOR pathway activation but showed no effect on viability. mTORC1/2 inhibitor treatment decreased NRG1 expression and downregulated ERBB3 while re-activating pAkt T308, suggesting a mechanism independent of NRG1-ERBB3 but likely involving activation of another upstream receptor kinase. Transcriptomics after mTORC1/2 inhibition confirmed decreased ERBB3/ERBB4 while revealing increased expression of insulin-like growth factor receptor 1 (IGF1R). Drug treatment co-targeting mTORC1/2 and IGF1R/insulin receptor attenuated pAkt T308 and showed synergistic effects on viability. Our findings indicate potential autocrine signaling where NF2 loss leads to secretion/activation of NRG1-ERBB3 signaling. mTORC1/2 inhibition downregulates NRG1-ERBB3, while upregulating pAkt T308 through an adaptive response involving IGF1R/insulin receptor and co-targeting these pathways may prove effective for treatment of NF2-deficient MN.

Programmed death ligand 1 and tumor-infiltrating CD8+ T lymphocytes are associated with the clinical features in meningioma.

OBJECTIVE: To investigate the expression of programmed death ligand-1 (PD-L1) and the levels of CD8+ tumor-infiltrating lymphocytes (TILs) in meningioma as well as determine the association between their levels and the clinical outcomes. METHODS: We performed a retrospective case-control study on 93 patients with meningioma. The patients showed tumor recurrence and were matched with the control patients without recurrence in their age, gender, admission time, tumor sites, tumor volume, peritumoral brain edema (PTBE), Simpson grade resection, WHO grade, postoperative radiotherapy, and the follow-up duration. We reviewed the clinical data of patients and performed immunohistochemistry analysis to investigate the PD-L1 expression and the levels of CD8+ TILs. Multivariate logistic regression was performed to analyze the association between clinical features and immune markers. The conditional logistic regression models were used to calculate the odds ratios (ORs) with 95% confidence intervals (CIs), and Kaplan-Meier analysis was performed to analyze tumor recurrence. RESULTS: Tumor volume was correlated with the PD-L1 expression (P = 0.003, HR = 5.288, 95%CI, 1.786-15.651). PTBE served as an independent predictor of CD8+ TIL levels (P = 0.001, HR = 0.176, 95%CI 0.065-0.477). The levels of CD8+ TILs were associated with tumor recurrence (P = 0.020, OR = 0.325, 95%CI, 0.125-0.840). CONCLUSION: Tumor volume was associated with PD-L1 expression, and PTBE was an independent predictor of CD8+ TIL levels in meningioma. CD8+ TIL levels correlated with tumor recurrence in meningioma.

mTOR Signaling and Potential Therapeutic Targeting in Meningioma.

Meningiomas are the most frequent primary tumors arising in the central nervous system. They typically follow a benign course, with an excellent prognosis for grade I lesions through surgical intervention. Although radiotherapy is a good option for recurrent, progressive, or inoperable tumors, alternative treatments are very limited. mTOR is a protein complex with increasing therapeutical potential as a target in cancer. The current understanding of the mTOR pathway heavily involves it in the development of meningioma. Its activation is strongly dependent on PI3K/Akt signaling and the merlin protein. Both factors are commonly defective in meningioma cells, which indicates their likely function in tumor growth. Furthermore, regarding molecular tumorigenesis, the kinase activity of the mTORC1 complex inhibits many components of the autophagosome, such as the ULK1 or Beclin complexes. mTOR contributes to redox homeostasis, a vital component of neoplasia. Recent clinical trials have investigated novel chemotherapeutic agents for mTOR inhibition, showing promising results in resistant or recurrent meningiomas.

Glycation of benign meningioma cells leads to increased invasion.

Meningiomas are the most common non-malignant intracranial tumors. Like most tumors, meningiomas prefer anaerobic glycolysis for energy production (Warburg effect). This leads to an increased synthesis of the metabolite methylglyoxal (MGO). This metabolite is known to react with amino groups of proteins. This reaction is called glycation, thereby building advanced glycation endproducts (AGEs). In this study, we investigated the influence of glycation on two meningioma cell lines, representing the WHO grade I (BEN-MEN-1) and the WHO grade III (IOMM-Lee). Increasing MGO concentrations led to the formation of AGEs and decreased growth in both cell lines. When analyzing the influence of glycation on adhesion, chemotaxis and invasion, we could show that the glycation of meningioma cells resulted in increased invasive potential of the benign meningioma cell line, whereas the invasive potential of the malignant cell line was reduced. In addition, glycation increased the E-cadherin- and decreased the N-cadherin-expression in BEN-MEN-1 cells, but did not affect the cadherin-expression in IOMM-Lee cells.

GAB1 overexpression identifies hedgehog-activated anterior skull base meningiomas.

AIMS: Mutations activating the hedgehog (Hh) signalling pathway have been described in anterior skull base meningiomas, raising hope for the use of targeted therapies. However, identification of Hh-activated tumours is hampered by the lack of a reliable immunohistochemical marker. We report the evaluation of GAB1, an immunohistochemical marker used to detect Hh pathway activation in medulloblastoma, as a potential marker of Hh-activated meningiomas. METHODS: GAB1 staining was compared to SMO mutation detection with Sanger and NGS techniques as well as Hh pathway activation study through mRNA expression level analyses in a discovery set of 110 anterior skull base meningiomas and in a prospective validation set of 21 meningiomas. RESULTS: Using an expression score ranging from 0 to 400, we show that a cut-off score of 250 lead to excellent detection of Hh pathway mutations (sensitivity 100%, specificity 86%). The prospective validation set confirmed the excellent negative predictive value of GAB1 to exclude Hh-independent meningiomas. We describe a large series of 32 SMO-mutant meningiomas and define multiple ways of Hh activation, either through somatic mutations or associated with mutually co-exclusive sonic hedgehog (SHH) or Indian hedgehog (IHH) overexpression independent of the mutations. CONCLUSION: The assessment of GAB1 expression by an immunohistochemical score is a fast and cost-efficient tool to screen anterior skull base meningiomas for activation of the Hh pathway. It could facilitate the identification of selected cases amenable to sequencing for Hh pathway genes as predictive markers for targeted therapy.