Glioblastoma Growth Research Articles

Exosomal miR-142-3p from M1-polarized macrophages suppresses cell growth and immune escape in glioblastoma through regulating HMGB1-mediated PD-1/PD-L1 checkpoint.

Glioblastoma (GBM) is one of the most prevalent cancerous brain tumors. Former studies have reported that exosomes derived from M1-polarized macrophages (M1 exosomes) inhibit tumor occurrence and development through delivery of tumor suppressor genes. Also, microRNA-142-3p (miR-142-3p) has been verified to function as a tumor suppressor. GBM cell proliferation was evaluated by Cell Counting Kit-8 (CCK-8), colony formation assay and 5-ethynyl-2'-deoxyuridine (EdU) assay; cell apoptosis was determined by flow cytometry analysis and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Mechanism investigations were conducted for analyzing the molecular mechanism by which miR-142-3p and M1 exosomes affect GBM progression. Upregulation of miR-142-3p expression was detected in M1-polarized macrophages and M1 exosomes. M1 exosomes inhibit GBM cell proliferation and trigger cell apoptosis. Functionally, miR-142-3p silencing promotes the proliferation and inhibits the apoptosis of GBM cells treated with M1 exosomes. As for molecular mechanism, miR-142-3p inhibits GBM cell growth via targeting high-mobility group box1 (HMGB1). In addition, miR-142-3p/HMGB1 axis affects GBM cell immune escape through modulation of programmed death-1/programmed death ligand-1 (PD-1/PD-L1) checkpoint. Our study demonstrated that exosomal miR-142-3p from M1-polarized macrophages suppresses cell growth and immune escape in GBM through regulating HMGB1-mediated PD-1/PD-L1 checkpoint.

Human protoxin PSCA inhibits growth and invasion of glioblastoma

Human protoxin PSCA inhibits growth and invasion of glioblastoma

RNF122 promotes glioblastoma growth via the JAK2/STAT3/c-Myc signaling Axis.

The E3 ubiquitin ligase is well recognized as a significant contributor to glioblastoma (GBM) progression and has promise as a prospective therapeutic target. This study explores the contribution of E3 ubiquitin ligase RNF122 in the GBM progression and the related molecular mechanisms. RNF122 expression levels were evaluated using qRT-PCR, WB, and IHC, while functional assays besides animal experiments were used to assess RNF122's effect on GBM progression. We also tested the RNF122 impact on JAK2/STAT3/c-Myc signaling using WB. RNF122 was upregulated in GBM and correlated to the advanced stage and poor clinical outcomes, representing an independent prognostic factor. Based on functional assays, RNF122 promotes GBM growth and cell cycle, which was validated further in subsequent analyses by JAK2/STAT3/c-Myc pathway activation. Moreover, JAK2/STAT3 signaling pathway inhibitor WP1066 can weaken the effect of overexpression RNF122 on promoting GBM progression. Our results revealed that RNF122 caused an aggressive phenotype to GBM and was a poor prognosticator; thus, targeting RNF122 may be effectual in GBM treatment.

B cell-based therapy produces antibodies that inhibit glioblastoma growth.

Glioblastoma (GBM) is a highly aggressive and malignant brain tumor with limited therapeutic options and a poor prognosis. Despite current treatments, the invasive nature of GBM often leads to recurrence. A promising alternative strategy is to harness the potential of the immune system against tumor cells. Our previous data showed that the BVax (B cell-based vaccine) can induce therapeutic responses in preclinical models of GBM. In this study, we aimed to characterize the antigenic reactivity of BVax-derived Abs and evaluate their therapeutic potential. We performed immunoproteomics and functional assays in murine models and samples from patients with GBM. Our investigations revealed that BVax distributed throughout the GBM tumor microenvironment and then differentiated into Ab-producing plasmablasts. Proteomics analyses indicated that the Abs produced by BVax had unique reactivity, predominantly targeting factors associated with cell motility and the extracellular matrix. Crucially, these Abs inhibited critical processes such as GBM cell migration and invasion. These findings provide valuable insights into the therapeutic potential of BVax-derived Abs for patients with GBM, pointing toward a novel direction for GBM immunotherapy.

Polymer-locking fusogenic liposomes for glioblastoma-targeted siRNA delivery and CRISPR-Cas gene editing.

In patients with glioblastoma (GBM), upregulated midkine (MDK) limits the survival benefits conferred by temozolomide (TMZ). RNA interference (RNAi) and CRISPR-Cas9 gene editing technology are attractive approaches for regulating MDK expression. However, delivering these biologics to GBM tissue is challenging. Here we demonstrate a polymer-locking fusogenic liposome (Plofsome) that can be transported across the blood-brain barrier (BBB) and deliver short interfering RNA or CRISPR-Cas9 ribonucleoprotein complexes into the cytoplasm of GBM cells. Plofsome is designed by integrating a 'lock' into the fusogenic liposome using a traceless reactive oxygen species (ROS)-cleavable linker so that fusion occurs only after crossing the BBB and entering the GBM tissue with high ROS levels. Our results showed that MDK suppression by Plofsomes significantly reduced TMZ resistance and inhibited GBM growth in orthotopic brain tumour models. Importantly, Plofsomes are effective only at tumour sites and not in normal tissues, which improves the safety of combined RNAi and CRISPR-Cas9 therapeutics.

Therapeutic Effect of 1,3‐Thiazin‐6‐One for the Treatment of Brain Cancer Through Increased Accumulation in the Brain Glioblastoma Cells

AbstractIn the present study a library of five (2‐(amino)‐1,3‐thiazin‐6‐one) compounds was synthesized and investigated as against glioblastoma cells in vitro and in vivo in the mice model. The results revealed that all of the five 1,3‐thiazin‐6‐one compounds (4a, 4b, 4c, 4d and 4e) exhibited cytotoxicity against U87MG and 9 L brain cancer cell lines. Moreover, it was found that 9 L cells showed slightly higher sensitivity towards the compounds 4a, 4b, 4c, 4d and 4e compared to U87MG cells. It was observed that the compounds 4a, 4b, 4c, 4d and 4e showed a time‐dependent increase in uptake efficiency by U87MG and 9 L cells. Furthermore, the data revealed that uptake of the compounds and therefore internalization was maximum during initial 1 h of the treatment. Among the synthesized compounds, compound 4c containing trifluoromethyl moiety showed higher uptake efficiency compared to the compound 4a, 4b, 4d and 4e. Treatment of U87MG and 9 L cell tumor spheroids with compound 4c significantly (P<0.05) inhibited the tumor growth compared to the control spheroids. In vivo data revealed that treatment with compound 4c led to a significant (P<0.05) decrease in glioblastoma growth in mice in dose‐dependent manner. Growth of glioblastoma in mice was almost completely inhibited after 28 days of treatment with 2 mg/kg dose of compound 4c. Pharmacokinetic studies showed that compound 4c remained in circulation for longer duration in mice and its terminal half‐life was found to be 6.5 h. Treatment of U87MG and 9 L cells with compound 4c led to a prominent decrease in expression of CYR61 protein. In conclusion, findings of the present study suggest that compound 4c acts as a potential therapeutic agent for the treatment of advanced brain cancer through activation of Hippo pathway. Therefore, more studies need to be performed to investigate the detailed mechanism underlying the inhibitory effect of compound 4c against the glioblastoma.

Deoxyarbutin targets mitochondria to trigger p53-dependent senescence of glioblastoma cells

Cellular senescence is a natural barrier of the transition from premalignant cells to invasive cancer. Pharmacological induction of senescence has been proposed as a possible anticancer strategy. In this study, we found that deoxyarbutin inhibited the growth of glioblastoma (GBM) cells by inducing cellular senescence, independent of tyrosinase expression. Instead, deoxyarbutin induced mitochondrial oxidative stress and damage. These aberrant mitochondria were key to the p53-dependent senescence of GBM cells. Facilitating autophagy or mitigating mitochondrial oxidative stress both suppressed p53 expression and alleviated cellular senescence induced by deoxyarbutin. Thus, our study reveals that deoxyarbutin induces mitochondrial oxidative stress to trigger the p53-dependent senescence of GBM cells. Importantly, deoxyarbutin treatment resulted in accumulation of p53, induction of cellular senescence, and inhibition of tumor growth in a subcutaneous tumor model of mouse. In conclusion, our study reveals that deoxyarbutin has therapeutic potential for GBM by inducing mitochondrial oxidative stress for p53-dependent senescence of GBM cells.

Microenvironment T-Type calcium channels regulate neuronal and glial processes to promote glioblastoma growth.

Background Glioblastoma (GBM) is the most common primary malignant brain tumor. The aim of this study was to elucidate the role of microenvironment and intrinsic T-type calcium channels (Cav3) in regulating tumor growth and progression. Methods We grafted syngeneic GBM cells into Cav3.2 knockout mice to assess the role of microenvironment T-Type calcium channels on GBM tumor growth. We performed single-cell RNA-seq (scRNA-seq) of tumors from WT and Cav3.2 KO mice to elucidate the regulation of tumors by the microenvironment. We used neurons from WT and Cav3.2 KO mice in co-culture with GBM stem cells (GSC) to assess the effects of Cav3.2 on neuron/GSC synaptic connections and tumor cell growth. Results Cav3.2 KO in the microenvironment led to significant reduction of GBM growth and prolongation of animal survival. scRNA-seq showed that microenvironment Cav3.2 regulates neuronal and glial biological processes. Microenvironment Cav3.2 downregulated numerous genes associated with regulating the OPC cell state in GBM tumors such as SOX10 and Olig2. Neuronal Cav3.2 promoted neuron/GSC synaptic connections and GSC growth. Treatment of GSCs with the Cav3 blocker mibefradil downregulated genes associated with neuronal processes. The Cav3 blocker drug mibefradil synergized with temozolomide (TMZ) and radiation to reduce in vivo tumor growth and prolong animal survival. Conclusions Together these data reveal a role for microenvironment Cav3 in promoting GBM tumor progression through regulating neuronal and glial processes particularly associated with the OPC-cell state. Targeting both intrinsic and microenvironment Cav3 with the inhibitor mibefradil significantly enhanced the anti-GBM effects of TMZ and radiation.

ORY-1001 inhibits glioblastoma cell growth by downregulating the Notch/HES1 pathway via suppressing lysine-specific demethylase 1 expression

To explore the inhibitory effect ORY-1001, a lysine-specific histone demethylase 1 (LSD1) inhibitor, on growth of glioblastoma (GBM) and the underlying mechanism. We analyzed LSD1 expressions in GBM and normal brain tissues based on data from TCGA and HPA databases. Female BALB/c mouse models bearing xenografts derived from U87 cells or cells with lentivirus-mediated LSD1 silencing or Notch overexpression were treated with saline or 400 µg/kg ORY-1001 by gavage every 7 days, and GBM formation and survival time of the mice were recorded. The effect of ORY-1001 on GBM cell viability was assessed, and its effect on LSD1 expression was analyzed with Western blotting. The genes and pathways associated with LSD1 were analyzed using bioinformatics methods. Western blotting and qRT-PCR were used to detect Notch/HES1 pathway expression after LSD1 silencing and ORY-1001 treatment. The impact of ORY-1001 on viability of U87 cells with Notch1 silencing or overexpression was assessed, and the regulatory effects of ORY-1001 on Notch/HES1 pathway were analyzed using chromatin immunoprecipitation assay. A high expression of LSD1 in GBM was negatively correlated with patient survival (P < 0.001). ORY-1001 and LSD1 silencing obviously reduced tumor burden and prolonged the survival time of GBM-bearing mice. ORY-1001 treatment significantly inhibited the viability and dose-dependently decreased LSD1 expression in GBM cells, and such inhibitory effect of ORY-1001 was attenuated by LSD1 silencing. The Notch pathway enriched the differential genes related to LSD1, and Notch/HES1 pathway expression was significantly down-regulated after LSD1 silencing and ORY-1001 treatment. Notch1 overexpression significantly attenuated the anti-tumor effect of ORY-1001 on GBM. Mechanistically, ORY-1001 disrupted the interaction between LSD1 and the Notch pathway target genes including Notch3, HES1 and CR2. ORY-1001 down-regulates the Notch/HES1 pathway by inhibiting LSD1 expression to suppress the growth of GBM in mice.

Stepwise-targeting and hypoxia-responsive liposome AMVY@NPs carrying siYAP and verteporfin for glioblastoma therapy

BackgroundThe Hippo pathway is a conserved tumour suppressor signalling pathway, and its dysregulation is often associated with abnormal cell growth and tumorigenesis. We previously revealed that the transcriptional coactivator Yes-associated protein (YAP), the key effector of the Hippo pathway, is a molecular target for glioblastoma (GBM), the most common malignant brain tumour. Inhibiting YAP with small interfering RNA (siYAP) or the specific inhibitor verteporfin (VP) can diminish GBM growth to a certain degree.ResultsIn this study, to enhance the anti-GBM effect of siYAP and VP, we designed stepwise-targeting and hypoxia-responsive liposomes (AMVY@NPs), which encapsulate hypoxia-responsive polymetronidazole-coated VP and DOTAP adsorbed siYAP, with angiopep-2 (A2) modification on the surface. AMVY@NPs exhibited excellent blood‒brain barrier crossing, GBM targeting, and hypoxia-responsive and efficient siYAP and VP release properties. By inhibiting the expression and function of YAP, AMVY@NPs synergistically inhibited both the growth and stemness of GBM in vitro. Moreover, AMVY@NPs strongly inhibited the growth of orthotopic U87 xenografts and improved the survival of tumour-bearing mice without adverse effects.ConclusionSpecific targeting of YAP with stepwise-targeting and hypoxia-responsive liposome AMVY@NPs carrying siYAP and VP efficiently inhibited GBM progression. This study provides a valuable drug delivery platform and creative insights for molecular targeted treatment of GBM in the future.

Pyrimidine compounds BY4003 and BY4008 inhibit glioblastoma cells growth via modulating JAK3/STAT3 signaling pathway

Glioblastoma (GBM) is a brain tumor characterized by its aggressive and invasive properties. It is found that STAT3 is abnormally activated in GBM, and inhibiting STAT3 signaling can effectively suppress tumor progression. In this study, novel pyrimidine compounds, BY4003 and BY4008, were synthesized to target the JAK3/STAT3 signaling pathway, and their therapeutic efficacy and mechanisms of action were evaluated and compared with Tofacitinib in U251, A172, LN428 and patient-derived glioblastoma cells. The ADP-Glo™ kinase assay was utilized to assessed the inhibitory effects of BY4003 and BY4008 on JAK3, a crucial member of the JAK family. The results showed that both compounds significantly inhibited JAK3 enzyme activity, with IC50 values in the nanomolar range. The antiproliferative effects of BY4003, BY4008, and Tofacitinib on GBM and patient-derived glioblastoma cells were evaluated by MTT and H&E assays. The impact of BY4003 and BY4008 on GBM cell migration and apoptosis induction was assessed through wound healing, transwell, and TUNEL assays. STAT3-regulated protein expression and relative mRNA levels were analyzed by western blotting, immunocytochemistry, immunofluorescence, and qRT-PCR. It was found that BY4003, BY4008 and Tofacitinib could inhibit U251, A172, LN428 and patient-derived glioblastoma cells growth and proliferation. Results showed decreased expression of STAT3-associated proteins, including p-STAT3, CyclinD1, and Bcl-2, and increased expression of Bax, a pro-apoptotic protein, as well as significant down-regulation of STAT3 and STAT3-related genes. These findings suggested that BY4003 and BY4008 could inhibit GBM growth by suppressing the JAK3/STAT3 signaling pathway, providing valuable insights into the therapeutic development of GBM.

Potential of GSPT1 as a novel target for glioblastoma therapy.

Glioblastoma is the most common malignant brain tumor in adults, the survival rate of which has not significantly improved over the past three decades. Therefore, there is an urgent need to develop novel treatment modalities. We previously reported that G1 to S phase transition 1 (GSPT1) depletion induces delayed cell cycle in primary astrocytes. Herein, we examined the potential of GSPT1 as a novel target for glioblastoma therapy. CC-885, a cereblon modulator that degrades GSPT1 by bridging GSPT1 to the CRL4 E3 ubiquitin ligase complex, was administered to nude mice with transplanted brain tumors of U87 glioblastoma cells. The survival period was significantly longer in CC-885 treated mice than in control mice. Furthermore, we generated GSPT1-knockout (KO) U87 cells and GSPT1-KO U87 cells with stable overexpression of FLAG-tagged GSPT1 (Rescued GSPT1-KO). Mice with transplanted GSPT1-KO U87 cells and Rescued GSPT1-KO U87 cells showed significantly longer and similar survival periods, respectively, as those with wild-type (WT) U87 cells. GSPT1-KO U87 cells showed enhanced apoptosis, detected by cleaved PARP1, compared to WT U87 cells. Brain tumors with transplantation of GSPT1-KO U87 cells also showed enhanced apoptosis compared to those with transplantation of WT and Rescued GSPT1-KO U87 cells. GSPT1 expression was confirmed in patients with glioblastoma. However, the clinical study using 87 glioblastoma samples showed that GSPT1 mRNA levels were not associated with overall survival. Taken together, we propose that GSPT1 is an essential protein for glioblastoma growth, but not its malignant characteristics, and that GSPT1 is a potential target for developing glioblastoma therapeutics.

Hybrid Nanoparticles Based on Mesoporous Silica and Functionalized Biopolymers as Drug Carriers for Chemotherapeutic Agents.

Mesoporous silica nanoparticles (MSNs) are promising drug carriers for cancer therapy. Their functionalization with ligands for specific tissue/cell targeting and stimuli-responsive cap materials for sealing drugs within the pores of MSNs is extensively studied for biomedical and pharmaceutical applications. The objective of the present work was to establish MSNs as ideal nanocarriers of anticancer drugs such as 5-FU and silymarin by exploiting characteristics such as their large surface area, pore size, and biocompatibility. Furthermore, coating with various biopolymeric materials such as carboxymethyl chitosan-dopamine and hyaluronic acid-folic acid on their surface would allow them to play the role of ligands in the process of active targeting to tumor cells in which there is an overexpression of specific receptors for them. From the results obtained, it emerged, in fact, that these hybrid nanoparticles not only inhibit the growth of glioblastoma and breast cancer cells, but also act as pH-responsive release systems potentially useful as release vectors in tumor environments.

CircVPS8 promotes the malignant phenotype and inhibits ferroptosis of glioma stem cells by acting as a scaffold for MKRN1, SOX15 and HNF4A.

Exciting breakthroughs have been achieved in the field of glioblastoma with therapeutic interventions targeting specific ferroptosis targets. Nonetheless, the precise mechanisms through which circRNAs regulate the ferroptosis pathway have yet to be fully elucidated. Here we have identified a novel circRNA, circVPS8, which is highly expressed in glioblastoma. Our findings demonstrated that circVPS8 enhances glioma stem cells' viability, proliferation, sphere-forming ability, and stemness. Additionally, it inhibits ferroptosis in GSCs. In vivo, experiments further supported the promotion of glioblastoma growth by circVPS8. Mechanistically, circVPS8 acts as a scaffold, binding to both MKRN1 and SOX15, thus facilitating the ubiquitination of MKRN1 and subsequent degradation of SOX15. Due to competitive binding, the ubiquitination ability of MKRN1 towards HNF4A is reduced, leading to elevated HNF4A expression. Increased HNF4A expression, along with decreased SOX15 expression, synergistically inhibits ferroptosis in glioblastoma. Overall, our study highlights circVPS8 as a promising therapeutic target and provides valuable insights for clinically targeted therapy of glioblastoma.

Folate receptor-targeted indomethacin-loaded gold nanoparticles enhance drug chemotherapeutic efficacy in glioblastoma cells and spheroids

Glioblastoma is a highly malignant brain cancer with a poor survival rate. Increasing evidence demonstrates the anticancer activity, including anti-glioma activity, of indomethacin (IND), a non-steroidal anti-inflammatory drug. However, due to the IND's poor aqueous solubility, nano-based drug delivery systems, especially gold nanoparticles (AuNPs), are great tools for increasing solubility and therapeutic efficacy. Herein, glutathione (GSH)-coated folic acid (FA)-modified AuNPs were used for the first time to generate IND-loaded AuNPs (55 nm), which were successfully synthesized according to DLS, TEM, FTIR, NMR, and TGA results. IND/AuNPs were found to have spherical morphology, nanoscale particle size, narrow size distribution, and good stability. Fluorescence and confocal imaging demonstrated that the nanoparticles penetrated folate receptor (FR)+ U-87MG human glioblastoma monolayer and sphere-forming cells. Remarkably, short-term exposure (4h) to IND/AuNPs significantly increased IND cytotoxicity in U-87MG cells after post-44h and -68h (>35- and >120-fold, respectively). Even against prolonged exposure of cells to IND for 24h, 48h, and 72h, IND/AuNP treatment revealed a marked result: glioma proliferation slowed by 7.38-fold, 6.8-fold, and 17-fold, respectively. No significant effect was observed on the FR− cell lines. The increased antitumoral activity was accompanied by efficient increased apoptosis in glioblastoma cells due to the IND/AuNP treatments. Moreover, compared to free-drug and control groups, IND/AuNP treatments markedly reduced glioblastoma growth in 3D spheroids (in vitro system that mimics in vivo tumors). Therefore, these findings suggest that the new spherical IND/Au-GSH-FA NP conjugate has the potential to be a beneficial therapeutic agent in glioblastoma therapy by targeting FRs.

Coordinated Targeting of S6K1/2 and AXL Disrupts Pyrimidine Biosynthesis in PTEN-Deficient Glioblastoma.

Therapy for glioblastoma would be advanced by incorporating molecularly targeted kinase-directed agents, similar to standard of care strategies in other tumor types. Here, we identify a kinase targeting approach to inhibit the metabolism and growth of glioblastoma.

AB043. BRD4 promotes immune escape of glioma cells by upregulating PD-L1 expression.

Glioblastoma multiforme (GBM) poses significant challenges in treatment due to its aggressive nature and immune escape mechanisms. Despite recent advances in immune checkpoint blockade therapies, GBM prognosis remains poor. The role of bromodomain and extraterminal domain protein 4 (BRD4) in GBM, especially its interaction with immune checkpoints, is not well understood. Bioinformatic gene expression and survival analysis for BRD4 was utilized in The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) databases. Clone formation assay, Transwell, Cell Counting Kit-8 (CCK8), and wound healing assay were utilized to validate BRD4's promotion of glioma cell proliferation, invasion, and migration. Chromatin immunoprecipitation (ChIP) assay was conducted to confirm BRD4 binding to the programmed death ligand 1 (PD-L1) promoter. A co-culture model was utilized with activated cluster of differentiation 8 (CD8)+ T cells and glioma cells. GL261 cells with BRD4 short hairpin RNA (shRNA) and/or PD-L1 cDNA were intracranially injected into mice to investigate tumor growth and survival time. Tumor tissue characteristics were analyzed using hematoxylin-eosin (H&E) and immunohistochemistry (IHC) staining and immune cell infiltration were assessed by flow cytometry. Bioinformatics analyses reveal elevated BRD4 expression in high-grade gliomas, correlating with poor patient survival. In vitro studies confirm that BRD4 promotes proliferation, invasion, and migration in GBM cells. BRD4 is a regulator of PD-L1 at the transcriptional level, implying its involvement in GBM's immune escape mechanisms. Co-culture experiments with CD8+ T cells demonstrate that BRD4 inhibition enhances tumor cell apoptosis. In vivo studies indicate that BRD4 knockout reduces immunosuppression, improves prognosis. Simultaneous manipulation of BRD4 and PD-L1 levels provides insights into their intertwined roles in shaping the immune landscape of GBM. BRD4 has the capability to regulate the growth of glioblastoma and enhance immune suppression by promoting PD-L1 expression. Targeting BRD4 represents a promising direction for future research and treatment.

AB046. Dual role of POSTN in maintaining glioblastoma stem cells and immune-suppressive microglia in glioblastoma.

Glioblastoma (GBM) is an immunosuppressive, universally lethal cancer driven by GBM stem cells (GSCs). The interplay between GSCs and the immunosuppressive microglia plays crucial roles in promoting malignant growth of GBM, however, the molecular mechanisms underlying this crosstalk are incompletely understood. We performed RNA sequencing to explore the mechanism by which periostin (POSTN) regulates GSCs and microglia. The biological function of POSTN in GBM development was confirmed in vitro and in vivo. Specifically, tumorsphere formation assay, proliferation analysis, migration assays, enzyme-linked immunosorbent assay, immunoblotting, and intracranial mouse model were performed. We identified POSTN secreted from GSCs promotes GSC self-renewal and tumor growth via activation of the αVβ3/phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/β-catenin/FOS like antigen 1 (FOSL1) pathway. In addition to its GSC intrinsic effects, POSTN is able to recruit microglia and upregulate cluster of differentiation 70 (CD70) expression through PI3K/AKT/nuclear factor-kappa B (NFκB) pathway in microglial cells, which in turn promotes the Treg development and functionality, and generates an immunosuppressive tumor microenvironment. Inhibition POSTN disrupts the GSC maintenance, inhibits recruitment of immunosuppressive microglial, reduces Treg development and function, and suppresses GBM growth, suggesting that targeting POSTN may effectively improve GBM treatment. In conclusion, our study defined POSTN as a key regulator in mediating the molecular crosstalk between GSCs and immune-suppressive Microglia in the tumor microenvironment in GBM. POSTN activates the PI3K/AKT/β-catenin/FOSL1 pathway in an autocrine manner to promote GSC self-renewal and tumor growth. At the same time, POSTN recruits microglia in a paracrine manner and upregulates the expression of CD70 in microglia through the PI3K/AKT/NFκB pathway, thereby promoting the development and function of Treg and generating an immunosuppressive tumor microenvironment. Our findings indicate that targeting the POSTN gene may be a promising approach to ablating GSCs, breaking the immunosuppressive environment and overcoming treatment resistance in GBM.

γ-aminobutyric acid receptor B signaling drives glioblastoma in females in an immune-dependent manner.

Sex differences in immune responses impact cancer outcomes and treatment response, including in glioblastoma (GBM). However, host factors underlying sex specific immune-cancer interactions are poorly understood. Here, we identify the neurotransmitter γ-aminobutyric acid (GABA) as a driver of GBM-promoting immune response in females. We demonstrated that GABA receptor B (GABBR) signaling enhances L-Arginine metabolism and nitric oxide synthase 2 (NOS2) expression in female granulocytic myeloid-derived suppressor cells (gMDSCs). GABBR agonist and GABA analog promoted GBM growth in females in an immune-dependent manner, while GABBR inhibition reduces gMDSC NOS2 production and extends survival only in females. Furthermore, female GBM patients have enriched GABA transcriptional signatures compared to males, and the use of GABA analogs in GBM patients is associated with worse short-term outcomes only in females. Collectively, these results highlight that GABA modulates anti-tumor immune response in a sex-specific manner, supporting future assessment of GABA pathway inhibitors as part of immunotherapy approaches.

UBE2D1 promotes glioblastoma proliferation by modulating p21 ubiquitination.

Glioblastoma (GBM) cells exhibit aberrant proliferative abilities and resistance to conventional therapies. However, the mechanisms underlying these malignant phenotypes are poorly understood. In this study, we identified ubiquitin-conjugating enzyme E2D1 (UBE2D1) as a crucial stimulator of GBM development. It is highly expressed in GBM and closely associated with poor prognosis in patients with GBM. UBE2D1 knockdown inhibits GBM cell growth and leads to G1 cell cycle arrest. Mechanistically, UBCH5A binds to p21 at the protein level and induces the ubiquitination and degradation of p21. This negative regulation is mediated by STUB1. Our findings are the first to identify UBE2D1 as a key driver of GBM growth and provide a potential target for improving prognosis and therapy.