Neuro-oncology最新文献

Background: Glioma is the most prevalent and lethal tumor of the central nervous system. Routine treatment with temozolomide (TMZ) would unfortunately result in inevitable recurrence and therapy resistance, severely limiting therapeutic efficacy. Tumor-associated astrocytes (TAAs) are key components of the tumor microenvironment and increasing evidence has demonstrated that aberrant expression of connexin43 (Cx43) was closely associated with glioma progression and TMZ resistance. However, the specific role of Cx43 in mediating TMZ resistance through glioma and astrocyte interactions has not been fully explored.

Methods: The expression and prognostic value of Cx43 were evaluated in tumor samples and clinical databases. ShRNA-medicated knockdown and Gfap-Cre Cx43flox/flox gene mouse were used to assess the role and functional significance of Cx43 in vitro and in vivo. Moreover, we performed mass spectrometry analysis, chromatin immunoprecipitation, and other biochemical assays to define the molecular mechanisms by which Cx43 promotes TMZ resistance.

Results: We confirmed that the upregulation of Cx43 expression between TAAs and glioma cells contributed to TMZ resistance and tumor recurrence. Genetic knockdown or pharmacological inhibition of Cx43 enhanced TMZ-induced cytotoxicity. Mechanistically, elevated Cx43 expression induced β-catenin accumulation at the cell surface of glioma cells, suppressing T-cell factor/lymphoid enhancer-binding factor transcription. This led to impaired miR-205-5p expression and subsequent activation of the E2F1/ERCC1 axis, which eventually led to chemoresistance.

Conclusions: Our study reveals a novel regulatory mechanism in which the Cx43/miR-205-5p/E2F1/ERCC1 axis contributes to TMZ resistance in glioma. These findings further highlight the potential of targeting Cx43 as a therapeutic strategy in glioma.

Background: Homozygous deletions of CDKN2A/B are known to predict poor prognosis in gliomas, but the impact of hemizygous deletions is less clear. This study aimed to evaluate the prognostic significance of hemizygous CDKN2A/B deletions in IDH-mutant low-grade astrocytomas and oligodendrogliomas.

Methods: Tissue samples diagnosed as astrocytoma, IDH-mutant and oligodendroglioma, IDH-mutant, 1p/19q co-deleted CNS WHO grade 2 and 3 were collected from the archives of the Institute of Neuropathology in Heidelberg. DNA methylation analysis was performed on formalin-fixed paraffin-embedded samples. Evaluation of the CDKN2A/B locus was performed by visual inspection of copy-number plots derived from methylation-array data for each case. Hemizygous and homozygous losses were assessed in relation to whole chromosomal or larger segmental losses and gains in the chromosomal profile. Survival probabilities were assessed using the Kaplan-Meier method.

Results: A total of 334 low-grade glioma cases were identified, including 173 astrocytomas and 161 oligodendrogliomas. Hemizygous deletions in CDKN2A/B (37/173 in astrocytomas, 15/161 in oligodendrogliomas) did not confer significantly worse survival outcomes compared to CDKN2A/B wild-type cases in neither low-grade astrocytoma (log-rank P = .2556; HR 2.29, 95% CI [0.76; 6.40], P = .135) nor oligodendroglioma (log-rank P = .2760; HR 0.17; 95% CI [0.01; 5.05]; P = .305), regardless of CNS WHO grade, which was further demonstrated on a subgroup of astrocytoma, IDH mutant CNS WHO 4 cases (log-rank P = .1680; HR 4.55, 95% CI [0.88; 24.51], P = .0689).

Conclusions: Hemizygous CDKN2A/B deletions do not significantly worsen OS or progression-free survival in IDH-mutant astrocytomas and oligodendrogliomas, CNS WHO grades 2 and 3.

Background: Primary central nervous system lymphoma (PCNSL) treatment relies on a high-dose methotrexate based chemotherapy (HD-MTX-based CT) regimen; however, whether there is a specific microbiota composition association with treatment response and clinical outcomes remains incompletely understood.

Methods: We conducted a prospective study of PCNSL patients, included in the clinical trial NCT02313389 and the ancillary study NCT04253496 from 2020 to 2023, where patients were treated with first line HD-MTX-based polychemotherapy without a consolidation treatment. Stool (n=52), cerebrospinal fluid (CSF, n=52), and plasma samples (n=35) were collected before and/or after therapy initiation to perform metagenomic, flow cytometry, and metabolomic analyses. Plasma metabolomic data of 90 patients also included in the BLOCAGE clinical trial was subsequently used as a validation cohort.

Results: Unsupervised clustering of microbial data identified two distinct gut microbial communities, differing in Parabacteroides distasonis abundance, which correlated with progression-free survival and overall survival in both uni- and multivariate analyses. Higher P. distasonis levels were linked to increased plasma betaine/valine metabolites and enhanced CD8 T cell infiltration in the CSF, suggesting a connection between gut microbiota and immune regulation. Stratifying the validation cohort by betaine/valine content confirmed these clinical associations.

Conclusions: Our findings suggest that gut microbiome communities modulate clinical outcomes in PCNSL patients undergoing standard treatment. Moreover, after future validation in external cohorts, the quantification of Parabacteroides distasonis could potentially provide a basis for patient stratification and guide personalized therapeutic strategies in the near future.

Background: In somatotroph tumors, over 50% of patients do not respond satisfactorily to the octreotide (OCT) treatment. Stimulation of SSTR2 with OCT triggers anti-proliferative signaling pathways mediated by the phosphatase SHP2. This phosphatase can exercise its functions through the STAT3, with the SHP2/STAT3 subcellular localization being crucial for understanding its mechanisms of action. We investigated the expression of SHP2 in somatotrophs tumors, the role of SHP2 on cell proliferation, its effects on STAT3 phosphorylation, and SHP2/STAT3 subcellular localization, using in vitro and a pre-clinical model.

Materials and methods: Protein and mRNA expression of SHP2 were evaluated in PitNETs by bioinformatic analysis, IHC and WB. The effect of SHP099 on cell proliferation was determined in GH3 cells, patient derived tumor cells and in a PDX model. The effect of SHP2 on STAT3, AKT and ERK1/2 activation was analyzed by WB, and SHP2/STAT3 subcellular localization was evaluated by IF and MET.

Results: We observed increased SHP2 expression in somatotroph tumors being associated with invasiveness. The anti-proliferative effect of OCT and its adaptation after long-term exposure may be driven by the expression of SSTR2 and SHP2. The treatment with SHP099 decreased cell proliferation, tumor volume growth, necrosis as well as the phosphorylation of STAT3-Tyr705, AKT and ERK1/2.

Conclusion: We have demonstrated that SHP2 is more expressed in somatotroph tumors, with its pharmacological inhibition resulting in a reduction of both in vitro and in vivo cell proliferation via STAT3 phosphorylation, making this phosphatase a novel clinical target with promising effects on somatotroph tumors.

Background: While international consensus and the 2021 WHO classification recognize multiple molecular medulloblastoma subgroups, these are difficult to identify in clinical practice utilizing routine approaches. As a result, biology-driven risk stratification and therapy assignment for medulloblastoma remains a major clinical challenge. Here, we report mass spectrometry-based analysis of clinical samples for medulloblastoma subgroup discovery, highlighting a MYC-driven prognostic signature and MYC immunohistochemistry (IHC) as a clinically tractable method for improved risk stratification.

Methods: We analyzed 56 formalin fixed paraffin embedded (FFPE) medulloblastoma samples by data independent acquisition mass spectrometry identifying a MYC proteome signature in therapy resistant Group 3 medulloblastoma. We validated MYC IHC prognostic and predictive value across two Group 3/4 medulloblastoma clinical cohorts (n=362) treated with standard therapies.

Results: After exclusion of WNT tumors, MYC IHC was an independent predictor of therapy resistance and death [HRs 23.6 and 3.23; 95% confidence interval (CI) 1.04-536.18 and 1.84-5.66; P = .047 and < .001]. Notably, only ~50% of the MYC IHC positive tumors harbored MYC amplification. Accordingly, cross-validated survival models incorporating MYC IHC outperformed current risk stratification schemes including MYC amplification, and reclassified ~20% of patients into a more appropriate very high-risk category.

Conclusion: This study provides a high-resolution proteomic dataset that can be used as a reference for future biomarker discovery. Biology-driven clinical trials should consider MYC IHC status in their design. Integration of MYC IHC in classification algorithms for non-WNT tumors could be rapidly adopted on a global scale, independently of advanced but technically challenging molecular profiling techniques.

Diffuse Midline Glioma (DMG) is a rare, aggressive, and fatal tumor that largely occurs in the pediatric population. To improve outcomes, it is important to characterize DMGs, which can be performed via MRI assessment. Recently, artificial intelligence (AI) and advanced imaging have demonstrated their potential to improve the evaluation of various brain tumors, gleaning more information from imaging data than is possible without these methods. This narrative review compiles the existing literature on the intersection of MRI-based AI use and DMG tumors. The applications of AI in DMG revolve around classification and diagnosis, segmentation, radiogenomics, and prognosis/survival prediction. Currently published articles have utilized a wide spectrum of AI algorithms, from traditional machine learning and radiomics to neural networks. Challenges include the lack of cohorts of DMG patients with publicly available, multi-institutional, multimodal imaging and genomics datasets as well as the overall rarity of the disease. As an adjunct to AI, advanced MRI techniques, including Diffusion Weighted Imaging (DWI), Perfusion Weighted Imaging (PWI), and Magnetic Resonance Spectroscopy (MRS), as well as Positron Emission Tomography (PET), provide additional insights into DMGs. Establishing AI models in conjunction with advanced imaging modalities has the potential to push clinical practice toward precision medicine.

The advent of molecular techniques has enhanced our understanding of the biology of malignancies over the past decade. Multi-omics has facilitated an in-depth characterization of glioblastomas at the cellular level, revealing intricate details about tumor cell states and their compositions. This advancement has substantially enriched our comprehension of tumor cell interactions with the surrounding microenvironment-such as neurons and immune cells-shedding light on patterns of tumor growth, infiltration, and therapeutic resistance. Despite the introduction of immunotherapies and molecularly guided chemotherapeutic treatments, surgical resection remains a cornerstone of glioblastoma therapeutic regimen. While maximal resection is universally considered to improve patient outcomes, integrating molecular data and insights into tumor cell interactions suggests a role for molecular-based surgical decision-making. Herein, we review how the molecular characterization of glioblastoma subtypes and their interactions can predict the benefits of surgical resection. We discuss how these insights could refine neurosurgical management in the future. Integrating multi-omics-preferably in real-time during surgery-promises to guide patient selection and optimize neurosurgical decision-making. Although these developments are promising for enhancing surgical strategies and improving patient outcomes, further validation in prospective studies involving larger cohorts and the development of workflows for clinical practice is needed.

Background: Glioblastoma (GBM) carries a poor prognosis, and new therapeutic strategies are necessary to improve outcomes for patients with this disease. Alkylating chemotherapies including temozolomide (TMZ) and lomustine (CCNU) are critical for treating GBM, but resistance mechanisms, including hypomethylation of O6-methylguanine-DNA methyltransferase (MGMT) promoter, undermine treatment. CRISPRoff is a programmable epigenetic memory editor that can induce stable and heritable gene silencing after transient delivery, and we hypothesize that CRISPRoff could potentiate the activity of TMZ and CCNU through long term suppression of target genes.

Methods: We transiently delivered CRISPRoff mRNA along with sgRNAs against target genes using both electroporation and lipid nanoparticles (LNPs) into established GBM cell lines, patient-derived primary GBM cultures, and orthotopic GBM xenografts. Gene repression, specificity, and stability was measured by RT-qPCR, Western blot, bisulfite sequencing, and RNA-sequencing. Sensitivity to chemotherapies was measured by cell viability dose response, microscopy, and bioluminescence imaging. Genome-wide mapping of CCNU sensitizers was performed using CRISPRi screens.

Results: CRISPRoff induced complete suppression of MGMT and sensitization to TMZ that were stable for over 8 months of continuous cell propagation. GBM orthotopic tumors treated with CRISPRoff against MGMT demonstrated sensitivity to TMZ in vivo, and CRISPRoff delivery resulted in chemosensitivity in patient-derived primary GBM. Genome-wide CRISPRi screens identified combinatorial genetic vulnerabilities (BRIP1, FANCE) that were targetable by multiplexed CRISPRoff to achieve sensitization to CCNU.

Conclusion: Transient delivery of a site-specific epigenetic memory can induce stable, complete, and multiplexed suppression of target genes for therapeutic application in GBM.

Background: Glioblastoma (GBM), a formidable and highly aggressive form of brain cancer, is predominantly driven by GBM stem cells (GSCs), which are characterized by their ability for self-renewal and aberrant differentiation. Targeting the terminal differentiation of GSCs represents a promising therapeutic strategy. This study aimed to elucidate the role of synapsin III (SYN3) in driving the differentiation of GSCs into neuron-like cells and its effect on the tumor-suppressive pathways in GBM.

Method: Proliferation assays, limited dilution assays, immunocytochemistry, western blot, RT-qPCR, and GSC tumor models were used to determine gene function and assess the role of γ-secretase inhibitors. Co-immunoprecipitation and microscale thermophoresis were conducted to explore the underlying regulatory mechanisms. Intracranial orthotopic injection of adeno-associated virus (AAV) was performed to evaluate therapeutic potential.

Results: We demonstrate that SYN3, uniquely within the synapsin family, acts as a tumor suppressor by steering GSCs toward neuronal-like transdifferentiation. Mechanistically, SYN3 enhances the expression of Neuregulin 3 (NRG3), which serves as a non-canonical antagonist of Notch signaling by competitively binding to specific epitopes within the EGF-like domain of JAG1, a critical site for the canonical engagement of Notch receptors. This critical interaction disrupts the JAG1-Notch1 signaling pathway, a key mechanism driving GSCs toward neuronal-like transdifferentiation, thereby reducing their stemness. Furthermore, SYN3 demonstrated significant antineoplastic activity in a mouse model harboring GSCs. AAV-mediated overexpression of SYN3 markedly impeded GBM progression.

Conclusion: Our research reveals the therapeutic potential of SYN3 in regulating GSC fate and offers a novel differentiation-based approach for GBM therapy.