Endothelial cell ferroptosis influences IDH wild-type glioblastoma growth in recurrent glioblastoma multiforme patients.

Glioblastomas are known for their poor clinical prognosis, with recurrent tumors often exhibiting greater invasiveness and faster growth rates compared to primary tumors. To understand the intratumoral changes driving this phenomenon, we employed single-cell sequencing to analyze the differences between two pairs of primary and recurrent glioblastomas. Our findings revealed an upregulation of ferroptosis in endothelial cells within recurrent tumors, identified by the significant overexpression of the NOX4 gene. Further analysis indicated that knocking down NOX4 in endothelial cells reduced the activity of the ferroptosis pathway. Utilizing conditioned media from endothelial cells with lower ferroptosis activity, we observed a decrease in the growth rate of glioblastoma cells. These results highlighted the complex role of ferroptosis within tumors and suggested that targeting ferroptosis in the treatment of glioblastomas requires careful consideration of its effects on endothelial cells, as it may otherwise produce counterproductive outcomes.

A case series of osseous metastases in patients with glioblastoma.

BACKGROUND: Extracranial metastases occur in <2% of cases of glioblastoma (GBM). When metastases do occur, bone is the most common destination. Herein, we review clinical characteristics of GBM patients with osseous metastases and evaluate both potential risk factors and prognostic significance. METHODS: Using an institutional database, we identified and retrospectively analyzed 6 patients with both GBM and osseous metastases. We collected data on patient demographics, tumor genetics, clinical courses, and outcomes. Given the rarity of metastatic GBM, we conducted historical comparisons using previously published literature. RESULTS: Five patients with osseous metastases (83%) were male, with a median age of 46 years at GBM diagnosis (range: 20-84). All patients had IDH-wildtype, MGMT promoter unmethylated GBM and 5 (83%) had alterations in TP53. All patients underwent surgical resection for GBM followed by radiation with concurrent and adjuvant temozolomide. Four patients (67%) received bevacizumab prior to bone metastasis diagnosis. Bone metastases were discovered at a median of 12.2 months (range: 5.3-35.2) after GBM diagnosis and 4.8 months after starting bevacizumab (range: 3.5-13.2). Three patients (50%) received immunotherapy. After osseous metastasis diagnosis, the median survival was 25 days (range: 13-225). CONCLUSION: In our cohort, most patients were male and young at the time of GBM diagnosis. All patients had IDH-wildtype, MGMT promoter unmethylated GBM, and most had alterations in TP53, which may be important for osseous metastasis. Most patients received bevacizumab, which has been associated with earlier metastasis. Osseous metastases of GBM occur and portend a dismal prognosis in an already aggressive malignancy.

Preoperative prediction of MGMT promoter methylation in glioblastoma based on multiregional and multi-sequence MRI radiomics analysis.

O6-methylguanine-DNA methyltransferase (MGMT) has been demonstrated to be an important prognostic and predictive marker in glioblastoma (GBM). To establish a reliable radiomics model based on MRI data to predict the MGMT promoter methylation status of GBM. A total of 183 patients with glioblastoma were included in this retrospective study. The visually accessible Rembrandt images (VASARI) features were extracted for each patient, and a total of 14676 multi-region features were extracted from enhanced, necrotic, "non-enhanced, and edematous" areas on their multiparametric MRI. Twelve individual radiomics models were constructed based on the radiomics features from different subregions and different sequences. Four single-sequence models, three single-region models and the combined radiomics model combining all individual models were constructed. Finally, the predictive performance of adding clinical factors and VASARI characteristics was evaluated. The ComRad model combining all individual radiomics models exhibited the best performance in test set 1 and test set 2, with the area under the receiver operating characteristic curve (AUC) of 0.839 (0.709-0.963) and 0.739 (0.581-0.897), respectively. The results indicated that the radiomics model combining multi-region and multi-parametric MRI features has exhibited promising performance in predicting MGMT methylation status in GBM. The Modeling scheme that combining all individual radiomics models showed best performance among all constructed moels.

Lysyl oxidase-like 1 predicts the prognosis of patients with primary glioblastoma and promotes tumor invasion via EMT pathway.

Background: Lysyl oxidase enzymes (LOXs), as extracellular matrix (ECM) protein regulators, play vital roles in tumor progression by remodeling the tumor microenvironment. However, their roles in glioblastoma (GBM) have not been fully elucidated. Methods: The genetic alterations and prognostic value of LOXs were investigated via cBioPortal. The correlations between LOXs and biological functions/molecular tumor subtypes were explored in The Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA). After Kaplan‒Meier and Cox survival analyses, a Loxl1-based nomogram and prognostic risk score model (PRSM) were constructed and evaluated by time-dependent receiver operating characteristic curves, calibration curves, and decision curve analyses. Tumor enrichment pathways and immune infiltrates were explored by single-cell RNA sequencing and TIMER. Loxl1-related changes in tumor viability/proliferation and invasion were further validated by CCK-8, western blot, wound healing, and Transwell invasion assays. Results: GBM patients with altered LOXs had poor survival. Upregulated LOXs were found in IDH1-wildtype and mesenchymal (not Loxl1) GBM subtypes, promoting ECM receptor interactions in GBM. The Loxl1-based nomogram and the PRSM showed high accuracy, reliability, and net clinical benefits. Loxl1 expression was related to tumor invasion and immune infiltration (B cells, neutrophils, and dendritic cells). Loxl1 knockdown suppressed GBM cell proliferation and invasion by inhibiting the EMT pathway (through the downregulation of N-cadherin/Vimentin/Snai1 and the upregulation of E-cadherin). Conclusion: The Loxl1-based nomogram and PRSM were stable and individualized for assessing GBM patient prognosis, and the invasive role of Loxl1 could provide a promising therapeutic strategy.

Multi-scale signaling and tumor evolution in high-grade gliomas.

Although genomic anomalies in glioblastoma (GBM) have been well studied for over a decade, its 5-year survival rate remains lower than 5%. We seek to expand the molecular landscape of high-grade glioma, composed of IDH-wildtype GBM and IDH-mutant grade 4 astrocytoma, by integrating proteomic, metabolomic, lipidomic, and post-translational modifications (PTMs) with genomic and transcriptomic measurements to uncover multi-scale regulatory interactions governing tumor development and evolution. Applying 14 proteogenomic and metabolomic platforms to 228 tumors (212 GBM and 16 grade 4 IDH-mutant astrocytoma), including 28 at recurrence, plus 18 normal brain samples and 14 brain metastases as comparators, reveals heterogeneous upstream alterations converging on common downstream events at the proteomic and metabolomic levels and changes in protein-protein interactions and glycosylation site occupancy at recurrence. Recurrent genetic alterations and phosphorylation events on PTPN11 map to important regulatory domains in three dimensions, suggesting a central role for PTPN11 signaling across high-grade gliomas.

The CEBPB+ glioblastoma subcluster specifically drives the formation of M2 tumor-associated macrophages to promote malignancy growth.

Rationale: The heterogeneity of tumor cells within the glioblastoma (GBM) microenvironment presents a complex challenge in curbing GBM progression. Understanding the specific mechanisms of interaction between different GBM cell subclusters and non-tumor cells is crucial. Methods: In this study, we utilized a comprehensive approach integrating glioma single-cell and spatial transcriptomics. This allowed us to examine the molecular interactions and spatial localization within GBM, focusing on a specific tumor cell subcluster, GBM subcluster 6, and M2-type tumor-associated macrophages (M2 TAMs). Results: Our analysis revealed a significant correlation between a specific tumor cell subcluster, GBM cluster 6, and M2-type TAMs. Further in vitro and in vivo experiments demonstrated the specific regulatory role of the CEBPB transcriptional network in GBM subcluster 6, which governs its tumorigenicity, recruitment of M2 TAMs, and polarization. This regulation involves molecules such as MCP1 for macrophage recruitment and the SPP1-Integrin αvß1-Akt signaling pathway for M2 polarization. Conclusion: Our findings not only deepen our understanding of the formation of M2 TAMs, particularly highlighting the differential roles played by heterogeneous cells within GBM in this process, but also provided new insights for effectively controlling the malignant progression of GBM.

Suppressing PD-L1 Expression via AURKA Kinase Inhibition Enhances Natural Killer Cell-Mediated Cytotoxicity against Glioblastoma.

Immunotherapies have shown significant promise as an impactful strategy in cancer treatment. However, in glioblastoma multiforme (GBM), the most prevalent primary brain tumor in adults, these therapies have demonstrated lower efficacy than initially anticipated. Consequently, there is an urgent need for strategies to enhance the effectiveness of immune treatments. AURKA has been identified as a potential drug target for GBM treatment. An analysis of the GBM cell transcriptome following AURKA inhibition revealed a potential influence on the immune system. Our research revealed that AURKA influenced PD-L1 levels in various GBM model systems in vitro and in vivo. Disrupting AURKA function genetically led to reduced PD-L1 levels and increased MHC-I expression in both established and patient-derived xenograft GBM cultures. This process involved both transcriptional and non-transcriptional pathways, partly implicating GSK3ß. Interfering with AURKA also enhanced NK-cell-mediated elimination of GBM by reducing PD-L1 expression, as evidenced in rescue experiments. Furthermore, using a mouse model that mimics GBM with patient-derived cells demonstrated that Alisertib decreased PD-L1 expression in living organisms. Combination therapy involving anti-PD-1 treatment and Alisertib significantly prolonged overall survival compared to vehicle treatment. These findings suggest that targeting AURKA could have therapeutic implications for modulating the immune environment within GBM cells.

Stanniocalcin-2 expression in glioblastoma - A novel prognostic biomarker: An observational study.

The objective of this study was to assess the prognostic relevance of Stanniocalcin-2 (STC2) expression, as determined via immunohistochemistry in tumor tissue, in a cohort of 83 patients diagnosed with glioblastoma who underwent maximal safe surgical resection followed by radiotherapy concurrent with adjuvant temozolomide. STC2 expression levels were categorized using a 3-tiered semiquantitative system: negative expression (level 0-), low expression (level 1+), and high expression (levels 2 + and 3+). Patients were categorized into 2 distinct groups according to their STC2 expression levels: negative STC2 (-/+) and positive STC2 (++/+++). The primary outcome measure was the relationship between STC2 expression and progression-free survival (PFS), with overall survival (OS) serving as the secondary endpoint. Kaplan-Meier survival analysis confirmed that patients exhibiting high STC2 expression had significantly shorter OS (8 vs 20 months, P < .001) and PFS (6 vs 18 months, P < .001) than those with low or negative STC2 expression. Multivariate analysis revealed that STC2 expression was an independent prognostic factor for both OS (hazard ratio: 0.4; 95% confidence interval: 0.2-0.8; P < .05) and PFS (hazard ratio: 0.3; 95% confidence interval: 0.2-0.4; P < .05) in patients with glioblastoma. Furthermore, elevated STC2 expression in GBM was correlated with several established aggressive clinicopathological characteristics, including advanced age (≥65 years), low ECOG PS (≥2), and isocitrate dehydrogenase mutation negativity. These findings underscore that heightened STC2 expression within the tumor tissue of GBM patients functions as an adverse prognostic marker, correlating with an elevated risk of progression and reduced OS. Therapeutic interventions targeting the AKT-mTOR, ERK1-2, and mitogen-activated protein kinase pathways as well as immune checkpoint inhibitors and vascular endothelial growth factor blockade, as well as potential forthcoming antibody-drug conjugates targeting the STC2 molecule, have the potential to broaden the scope of combined treatment strategies.

AGBL4 promotes malignant progression of glioblastoma via modulation of MMP-1 and inflammatory pathways.

Introduction: Glioblastoma multiforme (GBM), the most common primary malignant brain tumor, is notorious for its aggressive growth and dismal prognosis. This study aimed to elucidate the molecular underpinnings of GBM, particularly focusing on the role of AGBL4 and its connection to inflammatory pathways, to discover viable therapeutic targets. Methods: Single-cell sequencing was utilized to examine the expression levels of AGBL4 and functional assays were performed to assess the effects of AGBL4 modulation. Results: Our findings identified the significant upregulation of AGBL4 in GBM, which correlated with adverse clinical outcomes. Functional assays demonstrated that AGBL4 knockdown inhibited GBM cell proliferation, migration, and invasion and influenced inflammatory response pathways, while AGBL4 overexpression promoted these activities. Further investigation revealed that AGBL4 exerted its oncogenic effects through modulation of MMP-1, establishing a novel regulatory axis critical for GBM progression and inflammation. Discussion: Both AGBL4 and MMP-1 may be pivotal molecular targets, offering new avenues for targeted therapy in GBM management.

MicroRNAs as the pivotal regulators of Temozolomide resistance in glioblastoma.

Glioblastoma (GBM) is an aggressive nervous system tumor with a poor prognosis. Although, surgery, radiation therapy, and chemotherapy are the current standard protocol for GBM patients, there is still a poor prognosis in these patients. Temozolomide (TMZ) as a first-line therapeutic agent in GBM can easily cross from the blood-brain barrier to inhibit tumor cell proliferation. However, there is a high rate of TMZ resistance in GBM patients. Since, there are limited therapeutic choices for GBM patients who develop TMZ resistance; it is required to clarify the molecular mechanisms of chemo resistance to introduce the novel therapeutic targets. MicroRNAs (miRNAs) regulate chemo resistance through regulation of drug metabolism, absorption, DNA repair, apoptosis, and cell cycle. In the present review we discussed the role of miRNAs in TMZ response of GBM cells. It has been reported that miRNAs mainly induced TMZ sensitivity by regulation of signaling pathways and autophagy in GBM cells. Therefore, miRNAs can be used as the reliable diagnostic/prognostic markers in GBM patients. They can also be used as the therapeutic targets to improve the TMZ response in GBM cells.

Positive feedback loop of c-myc/XTP6/NDH2/NF-κB to promote malignant progression in glioblastoma.

BACKGROUND: Recent studies have highlighted the significant role of the NF-κB signaling pathway in the initiation and progression of cancer. Furthermore, long noncoding RNAs (lncRNAs) have been identified as pivotal regulators in sustaining the NF-κB signaling pathway's functionality. Despite these findings, the underlying molecular mechanisms through which lncRNAs influence the NF-κB pathway remain largely unexplored. METHODS: Bioinformatic analyses were utilized to investigate the differential expression and prognostic significance of XTP6. The functional roles of XTP6 were further elucidated through both in vitro and in vivo experimental approaches. To estimate the interaction between XTP6 and NDH2, RNA pulldown and RNA Immunoprecipitation (RIP) assays were conducted. The connection between XTP6 and the IκBα promoter was examined using Chromatin Isolation by RNA Purification (ChIRP) assays. Additionally, Chromatin Immunoprecipitation (ChIP) assays were implemented to analyze the binding affinity of c-myc to the XTP6 promoter, providing insights into the regulatory mechanisms at play. RESULTS: XTP6 was remarkedly upregulated in glioblastoma multiforme (GBM) tissues and was connected with adverse prognosis in GBM patients. Our investigations revealed that XTP6 can facilitate the malignant progression of GBM both in vitro and in vivo. Additionally, XTP6 downregulated IκBα expression by recruiting NDH2 to the IκBα promoter, which resulted in elevated levels of H3K27me3, thereby reducing the transcriptional activity of IκBα. Moreover, the progression of GBM was further driven by the c-myc-mediated upregulation of XTP6, establishing a positive feedback loop with IκBα that perpetuated the activation of the NF-κB signaling pathway. Notably, the application of an inhibitor targeting the NF-κB signaling pathway effectively inhibited the continuous activation induced by XTP6, leading to a significant reduction in tumor formation in vivo. CONCLUSION: The results reveal that XTP6 unveils an innovative epigenetic mechanism instrumental in the sustained activation of the NF-κB signaling pathway, suggesting a promising therapeutic target for the treatment of GBM.

Evaluation of secretome biomarkers in glioblastoma cancer stem cells: A bioinformatics analysis.

BACKGROUND: Glioblastoma (GBM) is a malignant brain tumor that frequently occurs alongside other central nervous system (CNS) conditions. The secretome of GBM cells contains a diverse array of proteins released into the extracellular space, influencing the tumor microenvironment. These proteins can serve as potential biomarkers for GBM due to their involvement in key biological processes, exploring the secretome biomarkers in GBM research represents a cutting-edge strategy with significant potential for advancing diagnostic precision, treatment monitoring, and ultimately improving outcomes for patients with this challenging brain cancer. AIM: This study was aimed to investigate the roles of secretome biomarkers and their pathwayes in GBM through bioinformatics analysis. METHODS AND RESULTS: Using data from the Gene Expression Omnibus and the Cancer Genome Atlas datasets-where both healthy and cancerous samples were analyzed-we used a quantitative analytical framework to identify differentially expressed genes (DEGs) and cell signaling pathways that might be related to GBM. Then, we performed gene ontology studies and hub protein identifications to estimate the roles of these DEGs after finding disease-gene connection networks and signaling pathways. Using the GEPIA Proportional Hazard Model and the Kaplan-Meier estimator, we widened our analysis to identify the important genes that may play a role in both progression and the survival of patients with GBM. In total, 890 DEGs, including 475 and 415 upregulated and downregulated were identified, respectively. Our results revealed that SQLE, DHCR7, delta-1 phospholipase C (PLCD1), and MINPP1 genes are highly expressed, and the Enolase 2 (ENO2) and hexokinase-1 (HK1) genes are low expressions. CONCLUSION: Hence, our findings suggest novel mechanisms that affect the occurrence of GBM development, growth, and/or establishment and may also serve as secretory biomarkers for GBM prognosis and possible targets for therapy. So, continued research in this field may uncover new avenues for therapeutic interventions and contribute to the ongoing efforts to combat GBM effectively.

Targeting drug resistance in glioblastoma (Review).

Glioblastoma (GBM) is the most common malignancy of the central nervous system in adults. The current standard of care includes surgery, radiation therapy, temozolomide; and tumor­treating fields leads to dismal overall survival. There are far limited treatments upon recurrence. Therapies to date are ineffective as a result of several factors, including the presence of the blood­brain barrier, blood tumor barrier, glioma stem­like cells and genetic heterogeneity in GBM. In the present review, the potential mechanisms that lead to treatment resistance in GBM and the measures which have been taken so far to attempt to overcome the resistance were discussed. The complex biology of GBM and lack of comprehensive understanding of the development of therapeutic resistance in GBM demands discovery of novel antigens that are targetable and provide effective therapeutic strategies.

ID2-ETS2 axis regulates the transcriptional acquisition of pro-tumoral microglia phenotype in glioma.

Glioblastoma is a highly aggressive brain tumour that creates an immunosuppressive microenvironment. Microglia, the brain's resident immune cells, play a crucial role in this environment. Glioblastoma cells can reprogramme microglia to create a supportive niche that promotes tumour growth. However, the mechanisms controlling the acquisition of a transcriptome associated with a tumour-supportive microglial reactive state are not fully understood. In this study, we investigated changes in the transcriptional profile of BV2 microglia exposed to C6 glioma cells. RNA-sequencing analysis revealed a significant upregulation of microglial inhibitor of DNA binding 1 (Id1) and Id2, helix-loop-helix negative transcription regulatory factors. The concomitant regulation of microglial ETS proto-oncogene 2, transcription factor (ETS2)-target genes, i.e., Dusp6, Fli1, Jun, Hmox1, and Stab1, led us to hypothesize that ETS2 could be regulated by ID proteins. In fact, ID2-ETS2 protein interactions increased in microglia exposed to glioma cells. In addition, perturbation of the ID2-ETS2 transcriptional axis influenced the acquisition of a microglial tumour-supportive phenotype. ID2 and ETS2 genes were found to be expressed by the tumour-associated microglia isolated from human glioblastoma tumour biopsies. Furthermore, ID2 and ETS2 gene expressions exhibited inverse prognostic values in patients with glioma in cohorts from The Cancer Genome Atlas. Collectively, our findings indicate that the regulation of ETS2 by ID2 plays a role in the transcriptional regulation of microglia in response to stimuli originating from glioblastoma cells, information that could lead to developing therapeutic strategies to manipulate microglial tumour-trophic functions.

Causal relationship between type 2 diabetes and glioblastoma: bidirectional Mendelian randomization analysis.

As the prevalence of Type 2 Diabetes Mellitus (T2DM) and Glioblastoma (GBM) rises globally, the relationship between T2DM and GBM remains controversial. This study aims to investigate whether genetically predicted T2DM is causally associated with GBM. We performed bidirectional Mendelian randomization (MR) analysis using data from genome-wide studies on T2DM (N = 62,892) and GBM (N = 218,792) in European populations. The results of the inverse-variance weighted (IVW) approach served as the primary outcomes. We applied Cochran's Q test and MR-Egger regression for heterogeneity assessment. Leave-one-out analysis was used to evaluate whether any single SNP significantly influenced the observed effect. Our findings reveal a significant causal association between T2DM and an increased risk of GBM (OR [95% CI] 1.70 [1.09, 2.65], P = 0.019). Conversely, the reverse association between T2DM and GBM was insignificant (OR [95% CI] 1.00 [0.99, 1.01], P = 0.408) (P > 0.40). Furthermore, the results from Cochran's Q-test and funnel plots in the MR-Egger method indicated no evidence of pleiotropy between the SNPs and GBM. Additionally, we mapped causal SNPs to genes and identified 10 genes, including MACF1, C1orf185, PTGFRN, NOTCH2, ABCB10, GCKR, THADA, RBMS1, SPHKAP, and PPARG, located on chromosomes 1, 2, and 3. These genes are involved in key biological processes such as the BMP signaling pathway and various metabolic pathways relevant to both conditions. This study provides robust evidence of a significant causal relationship between T2DM and an increased risk of GBM. The identified SNP-mapped genes highlight potential biological mechanisms underlying this association.

Chlorpromazine overcomes temozolomide resistance in glioblastoma by inhibiting Cx43 and essential DNA repair pathways.

BACKGROUND: In the fight against GBM, drug repurposing emerges as a viable and time-saving approach to explore new treatment options. Chlorpromazine, an old antipsychotic medication, has recently arisen as a promising candidate for repositioning in GBM therapy in addition to temozolomide, the first-line standard of care. We previously demonstrated the antitumor efficacy of chlorpromazine and its synergistic effects with temozolomide in suppressing GBM cell malignant features in vitro. This prompted us to accomplish a Phase II clinical trial to evaluate the efficacy and safety of adding chlorpromazine to temozolomide in GBM patients with unmethylated MGMT gene promoter. In this in vitro study, we investigate the potential role of chlorpromazine in overcoming temozolomide resistance. METHODS: In our experimental set, we analyzed Connexin-43 expression at both the transcriptional and protein levels in control- and chlorpromazine-treated GBM cells. DNA damage and subsequent repair were assessed by immunofluorescence of γ-H2AX and Reverse-Phase Protein microArrays in chlorpromazine treated GBM cell lines. To elucidate the relationship between DNA repair systems and chemoresistance, we analyzed a signature of DNA repair genes in GBM cells after treatment with chlorpromazine, temozolomide and Connexin-43 downregulation. RESULTS: Chlorpromazine treatment significantly downregulated connexin-43 expression in GBM cells, consequently compromising connexin-dependent cellular resilience, and ultimately contributing to cell death. In line with this, we observed concordant post-translational modifications of molecular determinants involved in DNA damage and repair pathways. Our evaluation of DNA repair genes revealed that temozolomide elicited an increase, while chlorpromazine, as well as connexin-43 silencing, a decrease in DNA repair gene expression in GBM cells. CONCLUSIONS: Chlorpromazine potentiates the cytotoxic effects of the alkylating agent temozolomide through a mechanism involving downregulation of Cx43 expression and disruption of the cell cycle arrest essential for DNA repair processes. This finding suggests that chlorpromazine may be a potential therapeutic strategy to overcome TMZ resistance in GBM cells by inhibiting their DNA repair mechanisms.

IKIP downregulates THBS1/FAK signaling to suppress migration and invasion by glioblastoma cells.

Background: Inhibitor of NF-κB kinase-interacting protein (IKIP) is known to promote proliferation of glioblastoma (GBM) cells, but how it affects migration and invasion by those cells is unclear. Methods: We compared levels of IKIP between glioma tissues and normal brain tissue in clinical samples and public databases. We examined the effects of IKIP overexpression and knockdown on the migration and invasion of GBM using transwell and wound healing assays, and we compared the transcriptomes under these different conditions to identify the molecular mechanisms involved. Results: Based on data from our clinical samples and from public databases, IKIP was overexpressed in GBM tumors, and its expression level correlated inversely with survival. IKIP overexpression in GBM cells inhibited migration and invasion in transwell and wound healing assays, whereas IKIP knockdown exerted the opposite effects. IKIP overexpression in GBM cells that were injected into mouse brain promoted tumor growth but inhibited tumor invasion of surrounding tissue. The effects of IKIP were associated with downregulation of THBS1 mRNA and concomitant inhibition of THBS1/FAK signaling. Conclusions: IKIP inhibits THBS1/FAK signaling to suppress migration and invasion of GBM cells.

Unveiling novel cell clusters and biomarkers in glioblastoma and its peritumoral microenvironment at the single-cell perspective.

BACKGROUND: Glioblastoma (GBM) is a highly heterogeneous, recurrent and aggressively invasive primary malignant brain tumor. The heterogeneity of GBM results in poor targeted therapy. Therefore, the aim of this study is to depict the cellular landscape of GBM and its peritumor from a single-cell perspective. Discovering new cell subtypes and biomarkers, and providing a theoretical basis for precision therapy. METHODS: We collected 8 tissue samples from 4 GBM patients to perform 10 × single-cell transcriptome sequencing. Quality control and filtering of data by Seurat package for clustering. Inferring copy number variations to identify malignant cells via the infercnv package. Functional enrichment analysis was performed by GSVA and clusterProfiler packages. STRING database and Cytoscape software were used to construct protein interaction networks. Inferring transcription factors by pySCENIC. Building cell differentiation trajectories via the monocle package. To infer intercellular communication networks by CellPhoneDB software. RESULTS: We observed that the tumor microenvironment (TME) varies among different locations and different GBM patients. We identified a proliferative cluster of oligodendrocytes with high expression of mitochondrial genes. We also identified two clusters of myeloid cells, one primarily located in the peritumor exhibiting an M1 phenotype with elevated TNFAIP8L3 expression, and another in the tumor and peritumor showing a proliferative tendency towards an M2 phenotype with increased DTL expression. We identified XIST, KCNH7, SYT1 and DIAPH3 as potential factors associated with the proliferation of malignant cells in GBM. CONCLUSIONS: These biomarkers and cell clusters we discovered may serve as targets for treatment. Targeted drugs developed against these biomarkers and cell clusters may enhance treatment efficacy, optimize immune therapy strategies, and improve the response rates of GBM patients to immunotherapy. Our findings provide a theoretical basis for the development of individualized treatment and precision medicine for GBM, which may be used to improve the survival of GBM patients.

Metastatic glioblastoma to the lungs: a case report and literature review.

Glioblastoma is the most common malignant primary brain tumor. Despite its infiltrative nature, extra-cranial glioblastoma metastases are rare. We present a case of a 63-year-old woman with metastatic glioblastoma in the lungs. Sarcomatous histology, a reported risk factor for disseminated disease, was found. Genomic alterations of TP53 mutation, TERT mutation, PTEN mutation, and +7/-10 were also uncovered. Early evidence suggests these molecular aberrations are common in metastatic glioblastoma. Treatment with third-line lenvatinib resulted in a mixed response. This case contributes to the growing body of evidence for the role of genomic alterations in predictive risk in metastatic glioblastoma. There remains an unmet need for treatment of metastatic glioblastoma.

Glioblastoma is the most common malignant primary brain tumor. Glioblastoma can spread into healthy tissue, but metastases beyond the brain are rare. We present a case of a 63-year-old woman with metastatic glioblastoma in the lungs. We identified risk factors associated with spread beyond the brain, including factors related to tissue structure and specific molecular alterations. Treatment with third-line lenvatinib resulted in a mixed response. This case adds to the limited existing data for the use of molecular alterations to serve as risk factors for metastatic glioblastoma. Treatment options are needed for this devastating disease.

Identification and validation of COL6A1 as a novel target for tumor electric field therapy in glioblastoma.

BACKGROUND: Glioblastoma multiforme (GBM) is the most aggressive primary brain malignancy. Novel therapeutic modalities like tumor electric field therapy (TEFT) have shown promise, but underlying mechanisms remain unclear. The extracellular matrix (ECM) is implicated in GBM progression, warranting investigation into TEFT-ECM interplay. METHODS: T98G cells were treated with TEFT (200 kHz, 2.2 V/m) for 72 h. Collagen type VI alpha 1 (COL6A1) was identified as hub gene via comprehensive bioinformatic analysis based on RNA sequencing (RNA-seq) and public glioma datasets. TEFT intervention models were established using T98G and Ln229 cell lines. Pre-TEFT and post-TEFT GBM tissues were collected for further validation. Focal adhesion pathway activity was assessed by western blot. Functional partners of COL6A1 were identified and validated by co-localization and survival analysis. RESULTS: TEFT altered ECM-related gene expression in T98G cells, including the hub gene COL6A1. COL6A1 was upregulated in GBM and associated with poor prognosis. Muti-database GBM single-cell analysis revealed high-COL6A1 expression predominantly in malignant cell subpopulations. Differential expression and functional enrichment analyses suggested COL6A1 might be involved in ECM organization and focal adhesion. Western blot (WB), immunofluorescence (IF), and co-immunoprecipitation (Co-IP) experiments revealed that TEFT significantly inhibited expression of COL6A1, hindering its interaction with ITGA5, consequently suppressing the FAK/Paxillin/AKT pathway activity. These results suggested that TEFT might exert its antitumor effects by downregulating COL6A1 and thereby inhibiting the activity of the focal adhesion pathway. CONCLUSION: TEFT could remodel the ECM of GBM cells by downregulating COL6A1 expression and inhibiting focal adhesion pathway. COL6A1 could interact with ITGA5 and activate the focal adhesion pathway, suggesting that it might be a potential therapeutic target mediating the antitumor effects of TEFT.