Background Despite the development of new treatment protocols for glioblastoma (GBM), temozolomide (TMZ) resistance remains a primary hindrance. Previous studies, including our study, have shown that aberrant N6‐methyladenosine (m 6 A) modification is implicated in GBM pathobiology. However, the roles and precise mechanisms of m 6 A modification in the regulation of TMZ resistance in GBM remain unclear. Methods m 6 A individual‐nucleotide‐resolution cross‐linking and immunoprecipitation sequencing (miCLIP‐seq) was performed to identify m 6 A modification of transcripts in TMZ‐resistant and ‐sensitive tumors. To explore the role of METTL3 in TMZ resistance, TMZ‐resistant GBM cells were transfected with METTL3 shRNA or overexpression lentivirus and then assessed by cell viability, tumor sphere formation, and apoptosis assays. An intracranial GBM xenograft model was developed to verify the effect of METTL3 depletion during TMZ treatment in vivo. ATAC‐seq, ChIP‐qPCR, and dual‐luciferase reporter assays were carried out to verify the role of SOX4/EZH2 in the modulation of METTL3 expression upon TMZ treatment. Results We demonstrated that TMZ treatment upregulated the expression of the m 6 A methyltransferase METTL3, thereby increasing m 6 A modification of histone modification‐related gene transcripts. METTL3 is required to maintain the features of GBM stem cells. When combined with TMZ, METTL3 silencing suppressed orthotopic TMZ‐resistant xenograft growth in a cooperative manner. Mechanistically, TMZ induced a SOX4‐mediated increase in chromatin accessibility at the METTL3 locus by promoting H3K27ac levels and recruiting RNA polymerase II. Moreover, METTL3 depletion affected the deposition of m 6 A on histone modification‐related gene transcripts, such as EZH2, leading to nonsense‐mediated mRNA decay. We revealed an important role of EZH2 in the regulation of METTL3 expression, which was via an H3K27me3 modification‐independent manner. Conclusions Our findings uncover the fundamental mechanisms underlying the interplay of m 6 A RNA modification and histone modification in TMZ resistance and emphasize the therapeutic potential of targeting the SOX4/EZH2/METTL3 axis in the treatment of TMZ‐resistant GBM.

High-grade meningioma has an unsatisfactory outcome despite surgery and postoperative radiotherapy; however, the factors driving its malignancy and recurrence remain largely unknown, which limits the development of systemic treatments. Single-cell RNA sequencing (scRNA-Seq) technology is a powerful tool for studying intratumoral cellular heterogeneity and revealing the roles of various cell types in oncogenesis. In this study, scRNA-Seq is used to identify a unique initiating cell subpopulation (SULT1E1 + ) in high-grade meningiomas. This subpopulation modulates the polarization of M2-type macrophages and promotes meningioma progression and recurrence. A novel patient-derived meningioma organoid (MO) model is established to characterize this unique subpopulation. The resulting MOs fully retain the aggressiveness of SULT1E1 + and exhibit invasiveness in the brain after orthotopic transplantation. By targeting SULT1E1 + in MOs, the synthetic compound SRT1720 is identified as a potential agent for systemic treatment and radiation sensitization. These findings shed light on the mechanism underlying the malignancy of high-grade meningiomas and provide a novel therapeutic target for refractory high-grade meningioma.

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Objective: Intracranial aneurysms presenting as third ventricular and adjoining parts masses are rare, and always associated with obstructive hydrocephalus. It is vital to provide precise diagnostics, and prompt treatment for such patients since endovascular or microsurgical operations remain challenging. This study aimed to discuss differential diagnosis tactic based on collected cases and the current literature on intracranial aneurysms mimicking third ventricular masses, and a treatment regimen based on the available data is proposed.Methods: We collected a case series of intracranial aneurysms presenting as third ventricular masses with hydrocephalus from our hospital database. Literature reports related to aneurysms adjoining the third ventricle since 1979 were also included.Results: Twenty-seven cases of this disease were collected. The average age of the patients was 62 years (range, 14–82 years). The female-to-male ratio of the patients was 14:13. Eight of the 27 patients died during hospitalization. Basilar artery aneurysm was the most common type (21 of 27 cases). One aneurysm from our cases was considered as a craniopharyngioma according to MRI report. There are false negative angiography reports for aneurysms from our cases and literature review. Strategies for the diagnosis and treatment of these aneurysms have changed over time. The uniqueness of our cases sheds light on the use of CT angiography, which has proven to be an appropriate test for diagnosis and reexamination but was not wildly applied in previous reports.Conclusions: Thrombosed aneurysms should be considered a differential diagnosis in patients with third ventricular masses. Application of CTA and VW-MRI can be beneficial. Aneurysm coil occlusion might be a favorable treatment for cases with mass effect. Further studies should be conducted to confirm our observations.

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