bluuebunny/crossref_metadata_2025_split huggingface dataset:
TMET-06. CLIP3 DOWNREGULATION LEADS TO RADIORESISTANCE IN GLIOBLASTOMA BY PROMOTING GLYCOLYTIC FLUX
Authors: Kim Dahye , Lee Haksoo , Kim Byeongsoo , Yum Soomin , Kang Wooseok , Kim HaYeon , Kang Hyunkoo , Youn HyeSook , Youn BuHyun 
Published: November 2024

Abstract
Glioblastoma Multiforme (GBM), a highly aggressive primary brain tumor, often develops resistance to standard treatments such as ionizing radiation (IR), which leads to a median survival of about 15 months. GBM contains glioblastoma stem cells (GSCs), which are crucial in driving therapeutic resistance and recurrence. In our study, we conducted comprehensive analyses to evaluate the molecular changes associated with radioresistance and explored the role of the Spy1-CLIP3 axis as a key regulator of GSC maintenance. Our methods included quantitative PCR and immunoblotting to measure CLIP3 mRNA and protein levels, revealing a significant reduction in expression among radioresistant GBM cells. We found that exposure to IR leads to the upregulation of Spy1 and downregulation of CLIP3, contributing to the development of radioresistance in surviving GBM cells. We used metabolic flux analysis techniques to observe changes in glycolytic activity, which increased in correlation with CLIP3 downregulation. IR induces CLIP3 downregulation, increasing glycolytic activity by facilitating the trafficking of GLUT3, the primary glucose transporter in GSCs. Additionally, colony-forming ability was evaluated using colony-forming assay after treatment of glimepiride with or without IR. Glimepiride didn’t reduce colony-forming ability in non-irradiated cells, but when combined with IR, it significantly reduced colony-forming ability, possibly by disrupting maintenance of GSCs. Importantly, our data reveal that glimepiride, a CLIP3 activator targets GSCs metabolism and enhances radiosensitization while maintaining low toxicity. The radioresistant GBM cells that survive radiotherapy exhibit increased stemness and glycolytic activity mediated by the Spy1-CLIP3 axis. Overall, our findings suggest that clinical trials using glimepiride for GBM patients may potentially improve survival rates, particularly for those experiencing recurrence after radiotherapy. This research highlights the importance of targeting cellular metabolism and stem cell properties in the context of GBM radioresistance and suggests potential avenues for improving the effectiveness of existing treatments.
TMET-09. SEX-BIASED ROLE OF TUMOR-ASSOCIATED MACROPHAGES IN GLIOBLASTOMA IRON METABOLISM
Authors: Pappus Sahu Aurosman , Palsa Kondaiah , Shenoy Ganesh , Slagle-Webb Becky , Connor James R 
Published: November 2024

Abstract
Glioblastoma (GBM) is an aggressive brain cancer that is extremely difficult to treat. GBM is sexually dimorphic in nature, where females are less susceptible to developing GBM, respond to therapy better, and get a survival advantage. Sex-biased differences in tumor iron metabolism play a significant part in making this disease sexually dimorphic. Macrophages constitute a significant population in the GBM tumor microenvironment and are key players in tumor iron homeostasis. Here, we examine macrophage iron homeostasis as a potential driver of sex biases in glioblastoma using bone marrow-derived macrophages (BMDM) isolated from C57BL/6 mice. Immunoblot analysis revealed higher ferritin L-chain (FTL) expression in male BMDM than in females (Fold change: 3.18, P = 0.02). Flow cytometric analysis revealed that male BMDMs had a significantly higher labile iron pool (LIP) (Fold change: 1.62, P = 0.0081). We used a stable isotope of iron (Fe57) to determine macrophage iron uptake by ICP-MS, and observed that male BMDMs have a higher iron uptake (fold change: 1.623, P = 0.0018) than females. These results indicate that macrophage iron metabolism is sexually dimorphic in nature. Next, we used a transwell co-culture system to study how macrophages regulate the iron status of GL261 cells. We found that GL261 cells had significantly lower H-Ferritin (FTH1) expression when co-cultured with male BMDMs (Fold change: 0.789, P = 0.0045). However, this decrease in ferritin didn’t result in a decrease in cellular LIP. We discovered that there was an increase in secreted ferritin in the GL261 culture media. Further experiments with Fe57-loaded GBM cells showed that this increase in secreted ferritin correlated with increased iron release from the GL261 cells. These results indicate that tumor-associated macrophages may regulate tumor iron homeostasis by inducing ferritin-bound iron release from GBM cells in a sex-biased manner.
TMET-17. LIPID METABOLIC HETEROGENEITY OF GLIOMA CELLULAR STATES REVEALS ENVIRONMENTAL DEPENDENCIES
Authors: Bayley Nicholas , Minami Jenna , Tse Christopher , Zhu Henan , Salinas Jennifer , Andrasz Cassidy , Yan Weihong , Cadet Dimitri , Borujerdpur Amir , Williams Kevin , Bhaduri Aparna , Bensinger Steven , Liau Linda , Cloughesy Timothy , Graeber Thomas , Nathanson David 
Published: November 2024

Abstract
Malignant growth and survival of cancer is supported through reprogrammed lipid metabolism. In gliomas, genetic alterations can drive lipid metabolic dysregulation revealing therapeutic opportunities to exploit lipid metabolic vulnerabilities within genetically defined subsets of glioma tumors. However, it remains unclear whether inter- and intra-tumoral transcriptomic heterogeneity in gliomas relates to distinct lipid programs and potential dependencies. Here we set out to characterize pan-glioma lipid metabolic heterogeneity through genomic, transcriptomic, and lipidomic profiling of a large and diverse cohort of patient tumor samples. We define key axes of lipid metabolic variability across gliomas and identify relationships between lipid metabolic gene expression programs and glioma lipidomic profiles. Intriguingly, intersection of lipid gene expression signatures with single cell RNA sequencing revealed patterns of lipid metabolic heterogeneity that distinguish neurodevelopmental cellular states of gliomas, mirroring patterns of lipid metabolic diversity across cell types within the normal brain. Consequently, tumors with opposing cellular state enrichment have distinct lipid metabolism and environmental dependencies. Tumors enriched for Radial Glia-like states have high capacity for de novo fatty acid synthesis while tumors enriched for oligodendrocyte progenitor-like states are dependent on exogenous sources of lipids for survival and growth. These findings connect inter- and intra-tumoral heterogeneity of cellular states to variability in lipid metabolic reprogramming to reveal future avenues for precision medicine.
TMET-24. MULTI-OMIC CHARACTERIZATION OF THE TEMPORAL METABOLIC ADAPTATIONS UNDERPINNING THERAPY RESISTANCE AND TUMOR RECURRENCE IN GLIOBLASTOMA
Authors: Martell Emma , Kuzmychova Helgi , Senthil Harshal , Kaul Esha , Chawla Ujala , Banerji Versha , Anderson Christopher M , Venugopal Chitra , Miller Donald , Werbowetski-Ogilvie Tamra E , Singh Sheila K , Sharif Tanveer 
Published: November 2024

Abstract
Therapy resistance and tumor recurrence are barriers to achieving long-term survival in cancer patients, particularly evident in glioblastoma (GBM), known for its dismal 5-year survival rate below 10%. Despite aggressive treatment regimens, including maximal resection, alkylating chemotherapy, and radiation, the majority of GBM patients experience relapse within 7-9 months post-initial intervention. Recurrent GBM poses surgical challenges and resists subsequent treatments, leading to an almost universally fatal outcome and an average survival of 12-18 months. Metabolic networks can serve as ancient stress-protection mechanisms that operate independently of genomic changes, offering an initial line of defense against exogenous pressures. Although the role of metabolism in cancer has gained prominence, our understanding of the metabolic adaptations following chemoradiotherapy and their contributions to therapy resistance and tumor recurrence in highly aggressive GBM tumors remains incomplete. We postulate that metabolic adaptations play a pivotal role in facilitating therapy resistance and GBM recurrence. Exploring the metabolic dependencies of these persistent cells may unveil vulnerabilities for therapeutic exploitation to counteract chemoradiotherapy resistance. We established clinically relevant patient-derived in vitro and in vivo models mirroring the standard GBM treatment protocol. Using state-of-the-art single-cell and bulk multi-omics technologies, we profiled the temporal transcriptomic and metabolomic adaptations from therapy-naïve primary GBM to chemoradiotherapy-resistant recurrent tumors. Our findings revealed unique metabolic transitions that occurred during chemoradiotherapy treatment in GBM cells that were conserved in vitro and in vivo across ten genetically diverse GBM patients. In a pre-clinical animal trial, a novel metabolism-targeting combinatorial treatment regimen prevented the emergence of recurrent tumors and significantly prolonged survival compared to chemoradiotherapy alone. Altogether, our results uncover distinct metabolic adaptations mediating therapy resistance and tumor recurrence in GBM. These findings emphasize the need to consider metabolic flexibility and dependencies for effective therapeutic strategies, offering potential avenues to overcome chemoresistance in recurrent GBM tumors.
TMET-35. UPREGULATION OF THE URIDINE SALVAGE PATHWAY IN MESENCHYMAL GLIOBLASTOMA STEM-LIKE CELLS
Authors: Baljinnyam Tuvshintugs , Sowers Mark L , Chang-Gu Bruce , Tang Hui , Herring Jason L , Zhang Kangling , Sowers Lawrence C 
Published: November 2024

Abstract
Glioblastoma is a heterogenous tumor comprised of multiple molecular subtypes of cancer cells and cancer stem-like cells. Of particular importance are the cancer stem-like cell niche population as they are believed to be more resistant to existing therapies and re-seed the tumor following initial response to standard-of-care treatment. To better understand glioblastoma stem-like cells we completed an untargeted proteomic analysis of 35 patient derived glioblastoma stem cell lines. This revealed an increase in several important proteins involved in the uridine salvage pathway, in the mesenchymal subtype. A subset of these proteins, including ecto-5’-nucleotidase (NT5E/CD73), uridine phosphorylase (UPP1), phosphoglucomutase-2-like-1 (PGM2L1), nicotinamide phosphoribosyltransferase (NAMPT), and nicotinamide N-methyltransferase (NNMT), suggest an augmented pathway for utilization of UMP and uridine as a fuel source and to replenish NAD+. Uridine and UMP are present in human serum and are enriched in the tumor microenvironment, providing a sustainable resource to resupply the tumor. The upregulation of this pathway was validated in established cell lines and orthogonal patient-derived xenograft cell lines not included in the proteomics study. Further work is underway to selectively inhibit or exploit this pathway with small molecule inhibitors.
TMET-36. INCREASED METHIONINE CYCLE DRIVES PYRIMIDINE METABOLISM IN LETHAL PEDIATRIC EPENDYMOMAS
Authors: Yadav Navneesh , Manuvel Antony Michealraj Kulandai 
Published: November 2024

Abstract
Supratentorial ependymomas (ST-EPN) are pediatric brain tumors found in the cerebral hemisphere, driven by the oncogenic fusion of ZFTA with RELA. Other than surgery and radiotherapy, these tumors do not have effective therapeutic options. Recurrent ST-EPN tumors are highly aggressive and hard to treat, which makes these tumors lethal. To understand the disease mechanism and potentially identify or develop therapeutic targets, we established patient-derived models and interrogated the genetic and metabolic dependencies using cutting-edge, near-genome-wide genetic screening and metabolomic tools. Our integrative transcriptomics and metabolic analysis identify that the ZFTA-RELA fusion drives methionine metabolic reprogramming in the cancer stem cells to regulate permissive epigenetic status and pyrimidine nucleotide synthesis to fuel tumor growth. Limiting methionine or inhibiting MAT2A, a rate-limiting enzyme of methionine metabolism in ST-EPN cells, results in profound cell cycle arrest and make the cells vulnerable to pyrimidine inhibitors compared to other pediatric brain tumors. Thus, for treatment, along with radiotherapy, blocking the methionine cycle by using the methionine limited diet or in combination with pyrimidine metabolism inhibitors can be a novel therapeutic strategy against the aggressive paediatric ST-EPN tumors.
TMET-38. BIOCHEMICAL CHARACTERIZATION OF PSAMMOMATOUS MENINGIOMA USING MAGNETIC RESONANCE SPECTROSCOPY
Authors: Ijare Omkar B , Powell Suzanne Z , Baskin David S , Pichumani Kumar 
Published: November 2024

Abstract
Psammomatous meningioma is a histologic subtype of meningioma and is presented as a highly calcified intracranial or spinal lesion. Although computed tomography (CT) and short/zero echo-time MRI techniques can detect calcification in tumors, a complete biochemical profile of psammomatous meningiomas is not known. Here, we compare the metabolomic profiles of common meningiomas (WHO grade-I and grade-II) and a psammomatous meningioma using ex vivo proton magnetic resonance spectroscopy (1H MRS). The tumor specimens were collected from meningioma patients undergoing surgery for the resection of the tumor mass. Tumor samples were extracted in 5% perchloric acid, centrifuged, supernatants were vacuum dried and reconstituted in D2O containing 1.0 mM sodium 2,2-dimethyl- 2-silapentane-5-sulfonate-d₆ (DSS-d6, internal standard). Previously, we have identified the following metabolites in grade-I and grade-II meningioma tumors: leucine, isoleucine, valine, lactate, alanine, acetate, glutamate, succinate, glutamine, aspartate, creatine, phosphocreatine, phosphocholine, glycerophosphocholine, myo-inositol, scyllo-inositol, taurine, hypotaurine, glycine, phosphoethanolamine, and glucose. In the current study, psammomatous meningioma also showed the presence of all the above metabolites; however, the levels of these metabolites were lower concentrations compared to the grade-I and grade-II meningiomas, except for lactate. In addition to the above-mentioned metabolites, psammomatous meningioma showed the presence of citrate which was not detected in other meningioma subtypes. Citrate is a major component of bone and the presence of citrate (~614 µM/g, tissue) in psammomatous meningioma could be due to the calcification occurring in these tumors. Surgical pathology report of resected tissue specimen showed clusters and small whorls of meningothelial cells with scattered calcifications, consistent with psammomatous meningioma (WHO grade-I; Ki-67 = 3%). In conclusion, detection of citrate by 1H MRS in meningiomas can be helpful in the differential diagnosis of psammomatous meningiomas.
TMIC-04. SPATIAL SEQUENCING OF MEDULLOBLASTOMA REVEALS BIOLOGICAL NICHES CORRELATED WITH HIGH-RISK FEATURES AND RELAPSE
Authors: Michaud Marina , Chien Franklin , Bakhtia Mojtaba , Snuderl Matija , Schroff Chanel , Schneiderjan Matthew , MacDonald Tobey , Bhasin Manoj 
Published: November 2024

Abstract
Medulloblastoma (MB) defines a heterogeneous set of neuroepithelial cancers of the posterior fossa. The MB tumor microenvironment (MB-TME) influences tumor progression and therapy response and has emerged as a growing target for novel therapeutic approaches. Prior single-cell analysis has characterized the MB-TME composition but does not reveal the spatial orientation of components. To address this gap, we performed 10X Visium spatial sequencing on sixteen pediatric MB samples obtained at surgical resection with samples representing the four molecular subtypes (WNT, N=1; SHH, N=6; Group 3, N=2; Group 4, N=5) and two matching samples at diagnosis and relapse. Spatial voxel clustering yielded clusters corresponding to malignant, immune, and stromal components of the TME, including tumor-associated astrocytes (TAAs), macrophages (TAMs), and vascular endothelium. Ten distinct clusters emerged representing malignant cell states, defined primarily by programs of cell cycle progression and neuronal differentiation. Notably, these MB cell clusters were differentially abundant between the MB subgroups, highlighting heterogeneity between disease subtypes. Moreover, examining the patterns of cellular spatial distribution in high-risk (HR) patients revealed dense regions of quiescent MB progenitors, while standard-risk patients showed greater heterogeneity within their TME. Proximity-dependent intercellular signaling further highlighted increased signaling by TAAs and vascular endothelium with decreased heat shock response signaling in HR patients. Comparing samples from relapse to diagnosis, TAMs, TAAs, and vascular endothelium were found to constitute a greater proportion of the TME. Subsequent niche-dependent gene expression and pathway analysis for TAAs localized near tumor vasculature in relapsed samples revealed increased expression of metastasis-associated pathways. Collectively, the results of our study enable new insight into the heterogeneity of the MB-TME, with close spatial association of quiescent MB progenitors correlating with high-risk clinical features. Quiescent MB progenitors have been documented to confer resistance through cellular dormancy, and identifying its molecular drivers may reveal potential targets for anticancer therapy.
TMIC-11. THE EFFECTIVENESS OF VALPROIC ACID IN COMBINATION WITH TEMOZOLOMIDE FOR TREATMENT OF HIGH-GRADE GLIOMAS: A SYSTEMATIC REVIEW AND META-ANALYSIS
Authors: Sharma Eshita , Ahmed Aisha Rizwan , Łajczak Paweł , Chatterjee Anoushka , Jagodzinski Maks , Rajab Numa , Sahin Oguz Kagan , Chawla Dikshit , Fagbamila Oluwaseun , Silva Yasmin , Petry Iago Nathan Simon , Fagundes Walter 
Published: November 2024

Abstract

BACKGROUND
High-grade gliomas (HGGs) rapidly progress with a high recurrence rate and poor prognosis despite standard multimodal treatment. Valproic acid (VPA), a histone deacetylase inhibitor, sensitizes HGG to radiochemotherapy along with having potential anti-cancer mechanisms and augmenting the growth inhibitory effect of Temozolomide (TMZ). This study explores the effectiveness of VPA in combination with TMZ for treating patients with HGG.

METHODS
A comprehensive literature search was performed on PubMed, Scopus, Embase, and Web of Science databases and identified relevant studies (case-control, cohort, RCTs) comparing the synergistic effect of VPA during TMZ to TMZ without VPA. We investigated median overall survival (OS), Progression-free survival (PFS), and baseline MGMT methylation status to evaluate this relationship.

RESULTS
Our systematic review encompassed 9 studies involving 4,097 patients with HGGs (seven cohorts, one case-control, and one RCT). The pooled analysis of median OS demonstrated no statistical significance difference between VPA during TMZ and TMZ alone (MD=-3.97; 95%CI=-8.43-0.49; p=0.08). However, sub-analysis showed a statistically significant effect in studies with sample size &lt;100 (MD=-5.06; 95%CI=-9.32,-0.80; p&lt;0.02), and 100-200 (MD=-7.07; 95%CI=-13.15,-1.00; p&lt;0.02), and those conducted before 2015 (MD=-5.62, 95%CI=-9.08,-2.17, p&lt;0.01). On meta-regression analysis, no statistical significance (RC=0.82,95% CI=0.39,-2.03, p=0.18) was observed, indicating that the study year is not associated with the intervention. A separate analysis of 3 studies also showed no significant variance in the baseline percentage of patients without MGMT methylation (log OR=-0.35, 95%CI=-1.02,-0.32, p=0.30) when administering VPA during TMZ treatment (n=67) compared to TMZ alone (n=409). Additionally, VPA during TMZ does not significantly affect PFS (MD=-3.54; 95% CI=-10.18-3.10, p=0.30) compared to TMZ alone.

CONCLUSIONS
The concurrent use of VPA with TMZ shows no significant effect on OS and PFS, nor does it show any variance in the baseline MGMT methylation status compared to TMZ alone. However, smaller sample sizes show a significant effect. Thus, our findings emphasize the imperative for additional research aimed at refining clinical outcomes.
TMIC-13. INTEGRATING SNRNASEQ AND SPATIAL TRANSCRIPTOME (ST) SHOWS DIVERSE TRANSCRIPTOMIC LANDSCAPE FOR TUMOR MICROENVIRONMENT (TME) IN INTRACRANIAL GERMINOMAS
Authors: Lin Na , Liu Anthony Pak-Yin , Ka-Wai Li Kay , Wong Queenie Hoi-Wing , Yang Rui Ryan , Chan Danny Tat-Ming , Ding Xiaofan , Ng Ho-Keung 
Published: November 2024

Abstract
The incidence of intracranial germ cell tumors is 5-8 times higher in East Asia and histologically, germinoma is well known to show intense lymphocytic infiltrates. In spite of germinoma’s well known immune infiltration, there have only been a few studies on its tumor micro-environment (TME). There has been no study using the recent and comprehensive techniques of single nucleus sequencing or spatial transcriptomics to study its TME. In this study, we studied snRNAseq (Chromium 10X) of FFPE tissues of 24 intracranial germinomas, and spatial transcriptomes (STs) (Visium Spatial) from fresh tissues from ten matched cases. For the TME, in contrast to common belief, macrophages and fibroblasts were equally represented as T- and NK-cells as immune cells. Clinical stage correlated with a lesser proportion of fibroblasts and T- and NK-cells. There was no correlation with proportion of tumor cells with either focal vs bifocal disease or clinical stage. Common gene modules (non-negative matrix factorization) were epithelial-mesenchymal transition (complete and partial), cell cycle and immune cells. Cell interaction analysis showed strong interaction between germ cells and macrophages involving CXCL, MIF and MK pathways. By ligand-receptor analysis, MIF combined with CD74 might promote tumor development. For ten cases, we studied STs with fresh tissues and integrated the results with snRNSeq, deconvoluting the spots for ST using snRNAseq cell types as reference (SPOTight) and achieved integrated single cell expression atlases of the STs (Seurat package). STs revealed a similar CNV plot pattern as those derived from snRNAseqs. Multimodal Intersection Analysis integrated significant genes based on snRNAseq and different regions’ significant genes based on STs. There was correlation between the expression of the four gene modules for tumor and immune cells for cell neighborhood. In conclusion, we showed in details the heterogenous expression landscape of TME of germinomas.