Glioblastoma Growth Research Articles

IMMU-06. H-FERRITIN AFFECTS IMMUNE CELL INFILTRATION INTO THE GLIOBLASTOMA TUMOR MICROENVIRONMENT IN A SEX-BIASED MANNER

Abstract Glioblastoma (GBM) is an aggressive brain cancer that is sexually dimorphic in nature, with females less susceptible to developing it, responding better to therapy, and gaining a survival advantage. Iron metabolism is also sexually dimorphic and has been shown previously to contribute to sex bias in GBM. Ferritin is an iron-storing protein that has elevated expression in tumor cells and is essential to GBM growth. Here, we used an in vivo GBM model consisting of heterozygous FTH1 knockdown (FTH1-KD) mice and GL261 cells to study the role of host ferritin in GBM progression. We have previously published that FTH1 knockdown in female mice decreased overall survival compared to WT (P = 0.03). This work delves into potential mechanisms that contribute to this survival difference. GBM was induced in 6-8 weeks-old mice by injecting 2*10^4 GL261 cells intracranially by a stereotaxic apparatus. The tumor volume was measured 3 weeks post-injection by magnetic resonance imaging, followed by image segmentation. We observed that FTH1 knockdown did not affect tumor volume. Flow cytometry was used to examine the immune infiltrating cells (CD45high) population in the tumor-bearing hemisphere. In females, there was an increase in CD11b+ cells in FTH1KD mice compared to WT mice (P = 0.0607). Similarly, Female FTH1-KD mice had a lower T cell (CD3+) population than Female WT mice (P = 0.0033). This decrease in infiltrating CD3 cells was due to a reduction of CD4 T cells (CD3+ CD4+) in female FTH1-KD mice compared to female WT mice (P = 0.0375). We observed no difference in CD8 T cells (CD3+ CD8+). These data indicate that host ferritin affects immune infiltration into GBM cells in a sex-biased manner.

CNSC-37. ROLE OF PGE2-REGULATED NEUROINFLAMMATION IN CONSTRUCTING NEURON-NK-GLIOMA CIRCUIT FOR GLIOBLASTOMA

Abstract Glioblastoma (GBM), known for its aggressive nature and poor prognosis, frequently recurs and resists standard treatments such as temozolomide (TMZ). This resistance is partly due to complex interactions within the tumor microenvironment, particularly involving neuronal excitation. Recent insights suggest that neuronal activity, through mechanisms like neurogliomal synapses, not only promotes glioma cell proliferation but also contributes to the chemoresistance observed in recurrent tumors. Our focus is on Prostaglandin E2 (PGE2), a mediator that regulates neuronal excitation, and its role in the recurrence and resistance of GBM. We discovered that PGE2 upregulates synaptic proteins and alters neurotransmitter profiles, enhancing tumor cell survival and resistance to TMZ. Specifically, increased levels of neurotransmitters such as glutamine and asparagine were observed in PGE2-rich environments, correlating with heightened chemoresistance and tumor recurrence. Co-culture experiments further demonstrated that PGE2-treated neuronal cells could induce resistance in adjacent GBM cells. These findings highlight the potential of targeting PGE2 pathways as a therapeutic strategy. A significant advancement in our study was the development and application of compound #038, a novel celecoxib derivative designed to cross the blood-brain barrier (BBB). This compound demonstrated enhanced efficacy in inhibiting GBM growth and improving survival rates in mouse models, indicating its potential as an effective therapeutic agent against GBM.

TMIC-49. TUMOR-DERIVED SPERMIDINE DRIVES IMMUNE SUPPRESSION IN THE GLIOBLASTOMA MICROENVIRONMENT VIA CD8 T CELL DEPLETION AND FUNCTIONAL ATTENUATION

Abstract A hallmark of glioblastoma (GBM) is an immunosuppressive microenvironment that is partially driven by tumor cell-derived secreted factors, highlighting the need for a more complete understanding of local immune suppressive mechanism. Altered secreted metabolite levels are observed in the GBM microenvironment; specifically, spermidine (a polyamine), which functions to drive cell proliferation, apoptosis, T cell lineage commitment, and myeloid cell-mediated suppression. However, the direct link between GBM cell-derived spermidine and the tumor microenvironment has yet to be determined. In syngeneic mouse GBM models, spermidine levels were increased in the tumor microenvironment and exogenous administration of spermidine accelerated tumor aggressiveness in an immune dependent-manner. Mechanistically, spermidine administration increased apoptosis of CD8+ T-cells and generated an exhausted phenotype. When ornithine decarboxylase (ODC1, the rate limiting enzyme in spermidine synthesis), was knocked down in tumor cells, no direct effect was observed on tumor cell growth. However, there was an increase in time to tumor succumbence and a concomitant increase in CD8+ T-cells and decrease in CD8+ T cell exhaustion. In GBM patients, there was a negative correlation between ODC1 expression and CD8+ T-cells present near the tumor. Additionally, patients with a favorable prognosis had significantly lower intratumoral levels of spermidine compared to patients with a poor prognosis. Taken together, these results demonstrate that spermidine functions as a tumor cell-derived metabolite that drives tumor progression through reducing CD8+T cell number and altering their phenotype. These findings have clinical implications as clinical trials using a polyamine biosynthesis inhibitor alone have not been very effective in GBM patients, suggesting the need for additional combination immunotherapies. Finally, spermidine is also produced at prominent levels by commensal gut microbes as well as absorbed from consumption of foods such as mushrooms; investigation into how these distal spermidine sources impact GBM growth via the gut-brain axis is actively ongoing.

IMMU-22. TWIST1-MEDIATED ENDOTHELIAL PLASTICITY DRIVES GLIOBLASTOMA RESISTANCE TO CAR T IMMUNOTHERAPY

Abstract Glioblastoma (GBM) is the most common and most aggressive malignant primary brain tumor in adults. Among the most lethal human malignancies, GBM is highly resistant to cytotoxic treatments and molecularly targeted therapies, and also generally refractory to T cell–based immunotherapies, largely due to their immunologically cold nature, i.e., characterized by a paucity of tumor T cell infiltrates that result from the immunosuppressive microenvironment. Here, we identify a distinct mechanism driven by spatiotemporal interaction of leukocytes with tumor stromal cells, namely, mesenchymal-like population of endothelial cells (ECs) form an immunosuppressive vascular niche that regulates macrophage polarization and induces GBM resistance to CAR T immunotherapy. Our single-cell transcriptome analyses of human and mouse GBM tumors identify a subpopulation of ECs acquire robust immunosuppressive phonotypes to drive alternative macrophage polarization. These ECs are spatially localized proximately to immunosuppressive macrophages and selectively express Twist1. Furthermore, we reveal a Twist1/SATB1-mediated sequential transcriptional activation mechanism, through which Twist1+ tumor ECs produce osteopontin to locally promote immunosuppressive macrophage phenotypes. Genetic or pharmacological ablation of Twist1 reverses macrophage-mediated immunosuppression and enhances T cell infiltration and activation, leading to reduced GBM growth and extended mouse survival. Importantly, pharmacological inhibition and lipid nanoparticle-mediated targeted inactivation of Twist1 overcome GBM resistance to Egfrviii CAR T cell immunotherapy. Thus, these findings uncover a spatially restricted mechanism controlling vasculature-mediated tumor immunity and suggest that targeting endothelial Twist1 may offer exciting opportunities for GBM immunotherapy.

Overcoming therapeutic limitations in glioblastoma treatment: A nanocomposite inducing ferroptosis and oxeiptosis via Photodynamic therapy

Photodynamic therapy (PDT) is an effective treatment for glioblastoma (GBM) that activates photosensitizers to produce reactive oxygen species (ROS) while minimizing harm to normal tissues.However, the therapeutic outcomes of PDT are often unsatisfactory. This limitation arises partly from the challenges posed by the blood–brain barrier (BBB) in transporting photosensitizers and partly from the excessive levels of glutathione (GSH) in the tumor microenvironment (TME), which can neutralize ROS. Hypericin (HYP) has emerged as a promising photosensitizer for PDT due to its excellent photosensitizing properties and antitumor activity. Dysregulated iron metabolism is a hallmark of numerous cancers, including GBM. In this study, biodegradable tetra-sulfide-bound dendritic mesoporous organosilicas nanocomposite (NCs) modified with bovine serum albumin (BSA) were synthesized. NCs penetrates the BBB and selectively targets GBM by binding to secreted acidic protein acidic and rich in cysteine (SPARC), an albumin-binding receptor that is prominently expressed in both the BBB and GBM. Upon degradation in response to high GSH concentrations in the TME, the NCs release their payload while concurrently depleting GSH. Under laser irradiation, the ROS-generating agent HYP, loaded within the NCs, is combined with the ferroptosis inducer erastin to achieve a synergistic anti-GBM effect via PDT/ferroptosis. Additionally, the NCs induces oxeiptosis by regulating KEAP1/PGAM5/AIFM1 pathway. Consequently, NC inhibits GBM growth by inducing ferroptosis and oxeiptosis through excessive ROS production. This study demonstrates the potential of NCs to enhance the effectiveness of PDT, offering a promising therapeutic strategy for GBM patients.

Comprehensive gene set enrichment and variation analyses identify SUV39H1 as a potential prognostic biomarker for glioblastoma immunorelevance

Glioblastoma (GBM) is the most common intracranial malignancy. SUV39H1 encodes a histone H3 lysine 9 methyltransferase that acts as an oncogene in several cancers; however, its role in GBM remains unknown. We obtained GBM transcriptome and clinical data from The Cancer Genome Atlas (TCGA) database on the UCSC Xena platform to perform differential and enrichment analyses of genes in the SUV39H1 high- and low-expression groups to construct a prognostic risk model. Analysis of SUV39H1 related biological processes in GBM was performed by gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA). High- and low-risk subgroup mutation signatures were analyzed using maftools. Immune infiltration was evaluated using IOBR and CIBERSORT algorithms. We analyzed the cell types and intercellular communication networks in glioma stem cells (GSCs) using scRNA-seq. The effects on GBM cells and GSCs after inhibition of SUV39H1 were investigated in vitro. SUV39H1 was significantly overexpressed in GBM and associated with poor prognosis. SUV39H1-related differentially expressed genes were enriched in immune and inflammation related pathways, and GSEA revealed that these genes were significantly enriched in signaling pathways such as IL-18, oxidative phosphorylation, and regulation of TP53 activity. Mutational analysis revealed frequent alterations in TP53 and PTEN expression. In addition, the infiltration abundances of the five immune cell types were significantly different between the high- and low-expression groups. Analysis of cellular communication networks by scRNA-seq revealed a strong interaction between CRYAB-GSC and PTPRZ1-GSC in GSCs. In vitro experiments verified that knockdown of SUV39H1 inhibited the viability and proliferation of U87 and U251 glioblastoma cells and downregulated the expression of stemness markers Nestin and SOX2 in CSC1589 and TS576 GSC lines. Increased SUV39H1 expression is associated with immune cell infiltration and poor prognosis in patients with GBM. Inhibition of SUV39H1 restrains GBM growth and reduces the stem cell properties of GSC. Thus, SUV39H1 might be a prognostic predictor and immunotherapeutic target in patients with GBM.

ALDH1A3 Contributes to Radiation-Induced Inhibition of Self-Renewal and Promotes Proliferative Activity of p53-Deficient Glioblastoma Stem Cells at the Onset of Differentiation.

ALDH1A3 is a marker for mesenchymal glioblastomas characterized by a greater degree of aggressiveness compared to other major subtypes. ADH1A3 has been implicated in the regulation of stemness and radioresistance mediated by glioblastoma stem cells. Mechanisms by which ALDH1A3 promotes malignant progression of glioblastoma remain elusive posing a challenge for rationalization of ALDH1A3 targeting in glioblastoma, and it is also unclear how ALDH1A3 regulates glioblastoma cells stemness. Usage of different models with diverse genetic backgrounds and often unknown degree of stemness is one possible reason for discrepant views on the role of ALDH1A3 in glioblastoma stem cells. This study clarifies ALDH1A3 impacts on glioblastoma stem cells by modelling ALDH1A3 expression in an otherwise invariable genetic background with consideration of the impacts of inherent plasticity and proliferative changes associated with transitions between cell states. Our main finding is that ALDH1A3 exerts cell-state dependent impact on proliferation of glioblastoma stem cells. We provide evidence that ALDH1A3 augments radiation-induced inhibition of self-renewal and promotes the proliferation of differentiated GSC progenies. Congruent effects ALDH1A3 and radiation on self-renewal and proliferation provides a framework for promoting glioblastoma growth under radiation treatment.

ROR1 facilitates glioblastoma growth via stabilizing GRB2 to promote c-Fos expression in glioma stem cells.

Glioma stem cells (GSCs) are the root cause of tumorigenesis, recurrence, and therapeutic resistance in glioblastoma (GBM), the most prevalent and lethal type of primary adult brain malignancy. The exploitation of novel methods targeting GSCs is crucial for the treatment of GBM. In this study, we investigate the function of the novel ROR1-GRB2-c-Fos axis in GSCs maintenance and GBM progression. The expression characteristics of ROR1 in GBM and GSCs were assessed by bioinformatic analysis, patient specimens, and patient-derived GSCs. Lentivirus-mediated gene knockdown and overexpression were conducted to evaluate the effect of ROR1 on GSCs proliferation and self-renewal both in vitro and in vivo. The downstream signaling of ROR1 in GSCs maintenance was unbiasedly determined by RNA-seq and validated both in vitro and in vivo. Finally, rescue assays were performed to further validate the function of the ROR1-GRB2-c-Fos axis in GSCs maintenance and GBM progression. ROR1 is upregulated in GBM and preferentially expressed in GSCs. Disruption of ROR1 markedly impairs GSC proliferation and self-renewal, and inhibits GBM growth in vivo. Moreover, ROR1 stabilizes GRB2 by directly binding and reducing its lysosomal degradation, and ROR1 knockdown significantly inhibits GRB2/ERK/c-Fos signaling in GSCs. Importantly, ectopic expression of c-Fos counteracts the effects caused by ROR1 silencing both in vitro and in vivo. ROR1 plays essential roles in GSCs maintenance through binding to GRB2 and activation of ERK/c-Fos signaling, which highlights the therapeutic potential of targeting the ROR1-GRB2-c-Fos axis.

Postoperative Injection of a Triptolide-Preloaded Hydrogel Prevents the Recurrence of Glioblastoma by Dual-Pathway Activation of Ferroptosis.

Glioblastoma (GBM) recurrence leads to high mortality, which remains a major concern in clinical therapy. Herein, an injectable triptolide (TP)-preloaded hydrogel (TP@DNH) accompanied by a postoperative injection strategy is developed to prevent the recurrence of GBM. With a potential inhibitor of the NRF2/SLC7A11/GPX4 axis, it is demonstrated that TP can deactivate glutathione peroxidase 4 (GPX4) from the source of glutathione (GSH) biosynthesis, thereby activating ferroptosis in GBM cells by blocking the neutralization of intracellular lipid peroxide (LPO). Based on acid-sensitive Fe3+/tannic acid (TA) metal-phenolic networks (MPNs), the TP@DNH hydrogel can induce the effective generation of reactive oxygen species (ROS) through Fe3+/TA-mediated Fenton reaction and achieve controllable release of TP in resected GBM cavity. Due to ROS generation and GPX4 deactivation, postoperative injection of TP@DNH can achieve high-level ferroptosis through dual-pathway LPO accumulation, remarkably suppressing the growth of recurrent GBM and prolonging the overall survival in orthotopic GBM relapse mouse model. This work provides an alternative paradigm for regulating ferroptosis in the postoperative treatment of GBM.

A peptide encoded by upstream open reading frame of MYC binds to tropomyosin receptor kinase B and promotes glioblastoma growth in mice.

MYC promotes tumor growth through multiple mechanisms. Here, we show that, in human glioblastomas, the variant MYC transcript encodes a 114-amino acid peptide, MYC pre-mRNA encoded protein (MPEP), from the upstream open reading frame (uORF) MPEP. Secreted MPEP promotes patient-derived xenograft tumor growth in vivo, independent of MYC through direct binding, and activation of tropomyosin receptor kinase B (TRKB), which induces downstream AKT-mTOR signaling. Targeting MPEP through genetic ablation reduced growth of patient-derived 4121 and 3691 glioblastoma stem cells. Administration of an MPEP-neutralizing antibody in combination with a small-molecule TRKB inhibitor reduced glioblastoma growth in patient-derived xenograft tumor-bearing mice. The overexpression of MPEP in surgical glioblastoma specimens predicted a poor prognosis, supporting its clinical relevance. In summary, our results demonstrate that tumor-specific translation of a MYC-associated uORF promotes glioblastoma growth, suggesting a new therapeutic strategy for glioblastoma.

Key Genes Involved in the Beneficial Mechanism of Hyperbaric Oxygen for Glioblastoma and Predictive Indicators of Hyperbaric Oxygen Prolonging Survival in Glioblastoma Patients.

The prognosis of glioblastoma is poor, and therapy-resistance is largely attributed to intratumor hypoxia. Hyperbaric oxygen (HBO) effectively alleviates hypoxia. However, the sole role of HBO in glioblastoma remains controversial. We previously reported that HBO can promote apoptosis, shorten protrusions, and delay growth of glioblastoma, but the molecular mechanism is unclear. We aimed to test candidate genes in HBO-exposed glioblastoma cells and to analyze their correlation with the survival of glioblastoma patients. Glioblastoma cell lines exposed to repetitive HBO or normobaric air (NBA) were collected for RNA isolation and microarray data analysis. GO analysis, KEGG pathway analysis and survival analysis of the differentially expressed genes (DEGs) were performed. HBO not only inhibited hypoxia-inducing genes including CA9, FGF11, PPFIA4, TCAF2 and SLC2A12, but also regulated vascularization by downregulating the expression of COL1A1, COL8A1, COL12A1, RHOJ and FILIP1L, ultimately attenuated hypoxic microenvironment of glioblastoma. HBO attenuated inflammatory microenvironment by reducing the expression of NLRP2, CARD8, MYD88 and CD180. HBO prevented metastasis by downregulating the expression of NTM, CXCL12, CXCL13, CXCR4, CXCR5, CDC42, IGFBP3, IGFBP5, GPC6, MMP19, ADAMTS1, EFEMP1, PTBP3, NF1 and PDCD1. HBO upregulated the expression of BAK1, PPIF, DDIT3, TP53I11 and FAS, whereas downregulated the expression of MDM4 and SIVA1, thus promoting apoptosis. HBO upregulated the expression of CDC25A, MCM2, PCNA, RFC33, DSCC1 and CDC14A, whereas downregulated the expression of ASNS, CDK6, CDKN1B, PTBP3 and MAD2L1, thus inhibiting cell cycle progression. Among these DEGs, 17 indicator-genes of HBO prolonging survival were detected. HBO is beneficial for glioblastoma. Glioblastoma patients with these predictive indicators may prolong survival with HBO therapy. These potential therapeutic targets especially COL1A1, ADAMTS1 and PTBP3 deserve further validation.

Lnc-H19-derived protein shapes the immunosuppressive microenvironment of glioblastoma.

The immunosuppressive tumor microenvironment (TME) is a prominent feature of glioblastoma (GBM), the most lethal primary brain cancer resistant to current immunotherapies. The mechanisms underlying GBM-TME remain to be explored. We report that long non-coding RNA (LncRNA) H19 encodes an immune-related protein called H19-IRP. Functionally separated from H19 RNA, H19-IRP promotes GBM immunosuppression by binding to the CCL2 and Galectin-9 promoters and activating their transcription, thereby recruiting myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs), leading to Tcell exhaustion and an immunosuppressive GBM-TME. H19-IRP, overexpressed in clinical GBM samples, acts as a tumor-associated antigen (TAA) presented by major histocompatibility complex class I (MHC-I). A circular RNA vaccine targeting H19-IRP (circH19-vac) triggers a potent cytotoxic Tcell response against GBM and inhibits GBM growth. Our results highlight the unrevealed function of H19-IRP in creating immunosuppressive GBM-TME by recruiting MDSCs and TAMs, supporting the idea of targeting H19-IRP with cancer vaccine for GBM treatment.

Transient MRI changes and neurological deterioration in glioblastoma upon SARS-CoV-2 infection.

Little is known about the effect of SARS-CoV-2 infection on glioblastoma (GBM) growth, metabolism, and prognosis. Immunological changes within GBM tissue are potentially symptomatic, underlining the urgent need for a better understanding of this phenomenon. To date, the complex underlying biology has not been fully elucidated. A decisive role of the tumor microenvironment (TME) and the components of the immune system acting within it is assumed. Immunohistochemical staining of SARS-CoV-2 spike protein and immune cell infiltration of TME was performed on the tumor tissue of one patient. This patient developed hemiparesis 14 days after symptomatic SARS-CoV-2 infection, leading to tumor diagnosis. Subsequently and after biopsy, there was an unexpectedly good response to chemotherapy only. In looking for further evidence of the potential of SARS-CoV-2 to influence the course of GBM, two additional adult patients that had transient MRI changes and neurological deterioration following SARS-CoV-2 infection were evaluated. In the patient for whom neurological deterioration in the course of SARS-CoV-2 led to GBM diagnosis, immunohistochemistry revealed virus-specific protein accumulation in the tumor cells, microglial activation, and the formation of T-cell nodules. In the other two patients, the findings were compatible with symptomatic pseudoprogression that occurred in a temporal relationship with SARS-CoV-2 infection. The results indicate a possible association between clinically relevant changes in GBM biology and SARS-CoV-2 infection, with histological confirmation of SARS-CoV-2-associated changes within the tumor tissue. The exact pathomechanism and underlying inflammatory pathways require further investigation.

Bufotalin Induces Oxidative Stress-Mediated Apoptosis by Blocking the ITGB4/FAK/ERK Pathway in Glioblastoma.

Bufotalin (BT), a major active constituent of Chansu, has been found to possess multiple pharmacological activities. Although previous studies have shown that BT could inhibit the growth of glioblastoma (GBM), the safety of BT in vivo and the potential mechanism are still unclear. We conducted a systematic assessment to investigate the impact of BT on GBM cell viability, migration, invasion, and colony formation. Furthermore, in vivo results were obtained to evaluate the effect of BT on tumor growth. The preliminary findings of our study demonstrate the effective inhibition of GBM cell growth and subcutaneous tumor development in mice by BT, with tolerable levels of tolerance observed. Mechanistically, BT treatment induced mitochondrial dysfunction, bursts of reactive oxygen species (ROS), and subsequent cell apoptosis. More importantly, proteomic-based differentially expressed proteins analysis revealed a significant downregulation of integrin β4 (ITGB4) following BT treatment. Furthermore, our evidence suggested that the ITGB4/focal adhesion kinase (FAK)/extracellular signal-related kinase (ERK) pathway involved BT-induced apoptosis. Overall, our study demonstrates the anti-GBM effects of BT and elucidates the underlying mechanism, highlighting BT as a potential therapeutic option for GBM.

Feeding the wrath with myelin

Kloosterman and colleagues studied molecular and cellular changes during radiation therapy and disease recurrence across molecular subtypes of glioblastoma. They uncovered a distinct immune–cancer cell metabolic crosstalk during proneural/oligodendrocyte progenitor cell-like to mesenchymal-like transition, wherein macrophages feed on cholesterol-rich myelin debris to provide lipids to mesenchymal tumor cells, thereby fueling glioblastoma growth.

Glial-Cell-Line-Derived Neurotrophic Factor Promotes Glioblastoma Cell Migration and Invasion via the SMAD2/3-SERPINE1-Signaling Axis.

Glial-cell-line-derived neurotrophic factor (GDNF) is highly expressed and is involved in the malignant phenotype in glioblastomas (GBMs). However, uncovering its underlying mechanism for promoting GBM progression is still a challenging work. In this study, we found that serine protease inhibitor family E member 1 (SERPINE1) was a potential downstream gene of GDNF. Further experiments confirmed that SERPINE1 was highly expressed in GBM tissues and cells, and its levels of expression and secretion were enhanced by exogenous GDNF. SERPINE1 knockdown inhibited the migration and invasion of GBM cells promoted by GDNF. Mechanistically, GDNF increased SERPINE1 by promoting the phosphorylation of SMAD2/3. In vivo experiments demonstrated that GDNF facilitated GBM growth and the expressions of proteins related to migration and invasion via SERPINE1. Collectively, our findings revealed that GDNF upregulated SERPINE1 via the SMAD2/3-signaling pathway, thereby accelerating GBM cell migration and invasion. The present work presents a new mechanism of GDNF, supporting GBM development.

The multifaceted role of long non-coding RNA DLEU1 in cancer progression: implications for diagnosis and therapy

INTRODUCTION AND PURPOSE: Long non-coding RNAs are key regulators of gene expression and tumorigenesis. Deleted in leukemia 1 (DLEU1) is significant in cancer development. This article reviews DLEU1's role across cancers, assessing its diagnostic and therapeutic potential. METHODS: A review of scientific articles from PubMed and Google Scholar was conducted. DESCRIPTION OF THE STATE OF KNOWLEDGE: DLEU1 drives tumor growth in glioblastoma, esophageal, colorectal, and oral cancers by interacting with key miRNAs and genes, promoting malignancy. In breast and ovarian cancers, DLEU1 modulates migration and invasion via specific pathways. In cervical cancer, DLEU1 is linked to immune modulation and serves as a prognostic marker. SUMMARY: DLEU1 is a vital regulator in various cancers, offering potential as a diagnostic and therapeutic target.

Abstract C080: Glioma cell-mediated hyper-thrombotic tumor microenvironment drives glioblastoma growth

Abstract Cancer-related thrombosis is the second leading cause of death for cancer patients, including those with glioblastoma (GBM), the most common primary malignant brain tumor. Patients with GBM have a 30% risk of venous thromboembolism (VTE). High platelet counts, and increased platelet reactivity are associated with poor clinical outcomes in many cancers. While platelets are known to promote progression of tumors, the mechanisms by which these changes in platelet reactivity act as a driver for GBM progression is unknown. Our previous work demonstrated that a subpopulation of glioma cells activates platelets to promote GBM cell growth by intrinsically producing thrombin via a cell intrinsic functional coagulation cascade. These findings provided evidence that glioma cells can readily execute a highly liver-specific gene expression program that contributes to a hyper-thrombotic state in the GBM tumor microenvironment (TME). We now demonstrate thrombin and platelet expression in GBM patient specimen creates a hyper-thrombotic GBM tumor-microenvironment and that GBM patient platelets have increased reactivity compared to healthy patients. Further, genetic targeting of the intrinsic coagulation cascade, via knockdown of coagulation factor 11 (F11) and coagulation factor 12 (F12), reduces glioma cell growth and tumor formation while also decreasing the ability for glioma cells to activate platelets, subsequently decreasing the hyper-thrombotic state seen in the GBM tumor microenvironment. Our observations suggest that glioma cells execute a cell intrinsic coagulation mechanism to contribute to the hyper-thrombotic tumor-microenvironment seen in GBM and may shed light onto mechanisms of cancer associated thrombosis in not only GBM, but also other malignancies. Citation Format: George Bukenya, Anthony Sloan, Craig Horbinski, Anirban Sen Gupta, Scott Cameron, Justin Lathia. Glioma cell-mediated hyper-thrombotic tumor microenvironment drives glioblastoma growth [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C080.

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