Functional characterization of TSPAN7 as a novel indicator for immunotherapy in glioma.

Glioma is the most common primary malignant tumor of the central nervous system in clinical practice. Most adult diffuse gliomas have poor efficacy after standard treatment, especially glioblastoma. With the in-depth understanding of brain immune microenvironment, immunotherapy as a new treatment has attracted much attention. In this study, through analyzing a large number of glioma cohorts, we reported that TSPAN7, a member of the tetraspanin family, decreased in high-grade gliomas and low expression was associated with poor prognosis in glioma patients. Meanwhile, the expression pattern of TSPAN7 was verified in glioma clinical samples and glioma cell lines by qPCR, Western Blotting and immunofluorescence. In addition, functional enrichment analysis showed that cell proliferation, EMT, angiogenesis, DNA repair and MAPK signaling pathways were activated in the TSPAN7 lower expression subgroup. Lentiviral plasmids were used to overexpress TSPAN7 in U87 and LN229 glioma cell lines to explore the anti-tumor role of TSPAN7 in glioma. Moreover, by analyzing the relationship between TSPAN7 expression and immune cell infiltration in multiple datasets, we found that TSPAN7 was significantly negatively correlated with the immune infiltration of tumor-related macrophages, especially M2-type macrophages. Further analysis of immune checkpoints showed that, the expression level of TSPAN7 was negatively correlated with the expression of PD-1, PD-L1 and CTLA-4. Using an independent anti-PD-1 immunotherapy cohorts of GBM, we demonstrated that TSPAN7 expression may had a synergistic effect with PD-L1 on the response to immunotherapy. Based on the above findings, we speculate that TSPAN7 can serve as a biomarker for prognosis and a potential immunotherapy target in glioma patients.

Transcription factor ZBTB42 is a novel prognostic factor associated with immune cell infiltration in glioma.

Background: ZBTB42 is a transcription factor that belongs to the ZBTB transcript factor family and plays an important role in skeletal muscle development. Dysregulation of ZBTB42 expression can lead to a variety of diseases. However, the function of ZBTB42 in glioma development has not been studied by now. Methods: We analyzed the expression of ZBTB42 in LGG and GBM via the The Cancer Genome Atlas CGA and Chinese Glioma Genome Atlas database. Gene Ontology, KEGG, and GSVA analyses were performed to illustrate ZBTB42-related pathways. ESTIMATE and CIBERSORT were applied to calculate the immune score and immune cell proportion in glioma. One-class logistic regression OCLR algorithm was used to study the stemness of glioma. Multivariate Cox analysis was employed to detect the prognostic value of five ZBTB42-related genes. Results: Our results show that ZBTB42 is highly expressed in glioma and may be a promising prognostic factor for Low Grade Glioma and GBM. In addition, ZBTB42 is related to immune cell infiltration and may play a role in the immune suppression microenvironment. What's more, ZBTB42 is correlated with stem cell markers and positively associated with glioma stemness. Finally, a five genes nomogram based on ZBTB42 was constructed and has an effective prognosis prediction ability. Conclusion: We identify that ZBTB42 is a prognostic biomarker for Low Grade Glioma and GBM and its function is related to the suppressive tumor microenvironment and stemness of glioma.

A neurodevelopmental epigenetic programme mediated by SMARCD3-DAB1-Reelin signalling is hijacked to promote medulloblastoma metastasis.

How abnormal neurodevelopment relates to the tumour aggressiveness of medulloblastoma (MB), the most common type of embryonal tumour, remains elusive. Here we uncover a neurodevelopmental epigenomic programme that is hijacked to induce MB metastatic dissemination. Unsupervised analyses of integrated publicly available datasets with our newly generated data reveal that SMARCD3 (also known as BAF60C) regulates Disabled 1 (DAB1)-mediated Reelin signalling in Purkinje cell migration and MB metastasis by orchestrating cis-regulatory elements at the DAB1 locus. We further identify that a core set of transcription factors, enhancer of zeste homologue 2 (EZH2) and nuclear factor I X (NFIX), coordinates with the cis-regulatory elements at the SMARCD3 locus to form a chromatin hub to control SMARCD3 expression in the developing cerebellum and in metastatic MB. Increased SMARCD3 expression activates Reelin-DAB1-mediated Src kinase signalling, which results in a MB response to Src inhibition. These data deepen our understanding of how neurodevelopmental programming influences disease progression and provide a potential therapeutic option for patients with MB.

Immune Infiltration Associated MAN2B1 Is a Novel Prognostic Biomarker for Glioma.

Mannosidase Alpha Class 2B Member 1 (MAN2B1) gene encodes lysosomal alpha-d-mannosidase involved in the ordered degradation of N-linked glycoproteins. Alteration in MAN2B1 has been proved to be accountable for several diseases. However, the relationship between MAN2B1 and glioma malignancy remains unclear. In this study, RNA-seq data from The Cancer Genome Atlas and the Chinese Glioma Genome Atlas datasets were analyzed to explore the correlation between MAN2B1 and clinicopathological features, prognosis, and somatic mutations in gliomas. We found that MAN2B1 was elevated in glioma and was correlated with malignant clinical and molecular features. Upregulated expression of MAN2B1 is prognostic for poor outcomes in glioma patients. Different frequencies of somatic mutations were found in gliomas between high and low MAN2B1 expression. Real-time quantitative polymerase chain reaction, western blot, and immunohistochemistry staining from glioma patient samples and cell lines were used to validate bioinformatic findings. Functional enrichment analysis showed that MAN2B1 was involved in immune and inflammation processes. Moreover, MAN2B1 expression was strongly correlated with M2 macrophages and weakly correlated with M1 macrophages. Further analysis confirmed that MAN2B1 was closely associated with the markers of M2 macrophages and tumor-associated macrophages. Taken together, MAN2B1 is a potential prognostic biomarker in glioma and associates with immune infiltration.