bluuebunny/crossref_metadata_2025_split huggingface dataset:
STEM-02. INSIGHTS INTO STEM CELL THERAPIES FOR GLIOBLASTOMA: A SYSTEMATIC REVIEW
Authors: UWISHEMA Olivier 
Published: November 2024

Abstract

BACKGROUND
Glioblastoma accounts for the majority of gliomas, which are the most common brain tumors. Classified as grade 4 by the WHO, it carries a poor prognosis. Various stem cell therapies have been tested and analyzed for their efficacy in treating glioblastoma. The aim of this review is to examine the type, efficacy, and future considerations for different stem cell therapies in glioblastoma treatment.

MATERIALS AND METHODS
A literature review was conducted using Boolean operators in the form of Stem Cell Therapy AND Glioblastoma; Neural Stem Cells AND Glioblastoma; Cord Blood AND Glioblastoma. Electronic databases including Cochrane Library, PubMed, and Scopus were searched. The review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 Statement.

RESULTS
Targeting Cancer Stem Cells (CSCs) may be crucial for effective GBM treatment, as these cells are considered key drivers of tumor initiation, progression, and therapeutic resistance. Future research and clinical trials in this area are necessary to fully understand the potential of stem cells in combating glioblastoma.

CONCLUSIONS
While some stem cell therapies have shown promising initial results, it is important to consider the complexity of targeting Glioblastoma Stem Cells (GSCs), including malignant transformation, the heterogeneity of glioblastoma, and glioma-associated mesenchymal stem cells.
STEM-04. UNVEILING GLIOBLASTOMA ORIGIN-CELLS: ISOLATION AND CHARACTERIZATION FROM THE SUBVENTRICULAR ZONE
Authors: Choi Ran Joo , Jo Se-Young , Yeo Eunchae , Oh Hyeong-Cheol , Jo Euna , Shim Jin-Kyung , Kim Hyun Jung , Lee Joo Ho , Yoo Jihwan , Choi Seonah , Moon Ju-Hyung , Kim Eui-Hyun , Kim Se Hoon , Chang Jong Hee , Kim Hyun Seok , Lee Jeong Ho , Kim Hoon , Kim Sangwoo , Kang Seok-Gu 
Published: November 2024

Abstract
Glioblastoma (GBM) may originate from somatic mutations within the subventricular zone (SVZ). We investigated putative GBM origin-cells in the SVZ with somatic mutations implicated in GBM development. We hypothesized these origin-cells have unique properties compared to tumor-derived GBM tumorspheres (TSs). We isolated, characterized, and analyzed mouse transcriptomes of GBM origin-cells and GBM TSs, and sought to identify potential human GBM origin-cells within the SVZ. Using a mouse model with somatic mutations (Trp53/Pten/hEGFRvIII) induced within the SVZ, we demonstrated that mutated cells in the SVZ migrate to the cortex and form GBM. We isolated mouse GBM (mGBM) origin-cells from the SVZ and mGBM TSs from the tumors, comparing their characteristics, transcriptome, and tumorigenic potential upon orthotopic or SVZ injection. To identify potential human GBM origin-cells, single-nucleus RNA sequencing (snRNAseq) was performed on human GBM SVZ specimens. Our investigation revealed intriguing properties and distinct gene expression patterns in GBM origin-cells. mGBM origin-cells from the SVZ somatic mutation model demonstrated enhanced stemness and invasiveness compared to control SVZ cells. These cells exhibited site-specific tumorigenic capacity: cortical injection of mGBM origin-cells failed to induce tumor formation, while re-injection into the SVZ led to migration to the cortex and tumor development. RNA sequencing revealed significant gene expression differences between mGBM origin-cells and mGBM TSs despite similar mutation profiles, suggesting distinct identities. snRNAseq analysis of human GBM SVZ specimens (pathologically tumor-free) identified cells with chromosomal aberrations characteristic of early GBM development, including chromosome 7 gain / 10 loss. These findings suggest potential human GBM origin-cells within the SVZ. This study describes a distinct population of GBM origin-cells within the SVZ, different from tumor-derived cancer stem cells. These GBM origin-cells exhibit unique properties, including enhanced stemness and invasiveness, and display site-specific tumorigenic capacity, forming tumors only in the SVZ environment. Further research into the factors that cause GBM origin-cells in the SVZ to migrate and form tumors in the cortex is crucial.
STEM-10. NEURAL PROGENITOR CELL MARKERS IN IDH MUTANT AND IDHWT GLIOMAS
Authors: Alnahhas Iyad , Kayne Allison , Khan Mehak , Shi Wenyin 
Published: November 2024

Abstract

INTRODUCTION
Single-cell RNA sequencing (scRNA-seq) has helped to elucidate the cellular composition of cancer and its microenvironment. Recent scRNA-seq studies have highlighted the heterogeneity of glioblastoma (GBM). Moreover, single-cell GBM analyses have proposed resemblance of GBM cells to radial glia and outer radial glia, supporting the hypothesis that remnants of developmental tissue get reactivated in cancer. A recent study isolated neural progenitor cells (NPCs) from developing fetal human brain (gestational week 17–19) and classified NPCs based on their expression of THY1, CD24 and EGFR. Ventricular radial glia are THY1- CD24-EGFR+ whereas outer radial glia are THY1- CD24-EGFR-. Early neuron precursors are CD24+THY1-EGFR+ and glial progenitor cells (GPCs) are THY1+EGFR+. GPCs give rise to THY1+EGFR+PDGFRA+ pre-oligodendrocyte progenitor cells. The importance of EGFR in NPCs again highlights the resemblance to glioma.

METHODS
We aimed to apply the classification above to IDH mutant astrocytoma and oligodendroglioma as well as IDHwt glioblastoma samples. We used three publicly available datasets: Wang (paired 74 IDHwt primary and recurrent samples), Tirosh (6 primary oligodendroglioma samples) and Venteicher (10 primary IDH mutant astrocytoma).

RESULTS
In IDH mutant astrocytoma, 82.63% of cells express THY1+ (mostly EGFR+PDGFRA+) and 10.76% of cells are THY1-CD24-EGFR+. In oligodendroglioma, 75% of cells are THY1+ (mostly EGFR+PDGFRA+) and 12.07% are THY1-CD24-EGFR+. In IDHwt EGFR amplified primary GBM samples, 87.5% of cells are THY1-CD24-EGFR+. This percentage drops to 70.4% in the recurrent setting. THY1-CD24-EGFR- cells increase from 9.7% to 23.1% at recurrence. In IDHwt EGFRwt primary GBM samples, 48.6% of cells are THY1-CD24-EGFR+ and 44.15% are THY1-CD24-EGFR-. In the recurrent setting, 43.26% of cells are THY1-CD24-EGFR+ and 49.58% are THY1-CD24-EGFR-.

CONCLUSION
IDH mutant gliomas and IDHwt glioblastoma express different progenitor cell markers and may have a different cell of origin. THY1 is highly expressed in IDH mutant gliomas.
STEM-19. TARGETINGGIHCG LNCRNA IN GLIOBLASTOMA STEM CELLS: A POTENTIAL THERAPEUTIC STRATEGY
Authors: Hazra Rasmani 
Published: November 2024

Abstract
Glioblastoma multiforme (GBM) remains the most lethal and prevalent primary brain tumor worldwide. Despite advances in understanding its biology and multimodal therapy options, the overall prognosis for GBM patients remains bleak, primarily due to the high recurrence rate, which is intimately linked to tumor resistance against standard therapeutic interventions. Glioblastoma stem cells (GSCs) contribute to therapeutic resistance and cellular heterogeneity through their self-renewal properties and ability to adapt. Thus, identifying new molecular targets driving GBM progression is crucial for developing effective therapies. Recent advancements in genome biology have revealed that long non-coding RNAs (lncRNAs) play roles in various biological functions, and the dysregulation of numerous lncRNAs has been shown to be associated with specific cancers. To identify GSC-associated lncRNAs, a comprehensive analysis was performed using single-cell RNA sequencing datasets from GBM tumors, GBM organoids, GSC-enriched GBM tumors, as well as normal human brain samples. A chromatin-enriched lncRNA, GIHCG, was identified as being highly expressed in GSCs compared to non-neoplastic neural stem cells. The GIHCG gene, located on human chromosome 12q14.1, is frequently amplified in glioblastoma and impacts overall survival. Bioinformatic and functional analyses revealed that GIHCG is amplified in 13% of GBM patient samples, and high expression of GIHCG is a negative prognostic marker for GBM patients, with significantly reduced overall survival compared to the low expression group. In addition, the depletion of GIHCG significantly reduced GSC proliferation and migration. Further, the knockdown of GIHCG decreased both mRNA and protein expression levels of critical GSC stemness factors, including SOX2, NESTIN, and OLIG2. Moreover, GIHCG depletion reduced the sphere formation capacity of GSCs, demonstrating the functional importance of GIHCG in the maintenance of GSC stemness. These results indicate that GIHCG is essential for GSC proliferation, migration, and stemness, underscoring its potential therapeutic value in RNA-based therapies for combating glioblastoma malignancy.
CSIG-12. YAP1-TEAD SIGNALING CONTRIBUTES TO LUNG CANCER COLONIZATION OF THE BRAIN
Authors: Torrini Consuelo , Nayyar Naema , Summers Elizabeth , Sasisekharan Varun , Wakimoto Hiroaki , Brastianos Priscilla 
Published: November 2024

Abstract

BACKGROUND
Lung cancer is the most common primary tumor to metastasize to the brain. Poor understanding of the brain metastasis process limits therapeutic options. Despite emerging data on the role of YAP signaling pathway in the development of brain tumors, a gap in knowledge remains regarding its role in brain colonization. We hypothesize that YAP1 and the associated TEAD transcriptional factors are responsible for lung cancer progression and that intervention with YAP/TEAD-targeted therapy will prevent brain dissemination.

METHODS
Lung cancer cells at different stages of cancer progression (VMRC-LCD and NCI-H1975, lung cancer cell lines; NCI-H1915 and LN001, brain metastatic cancer cells) were genetically engineered to overexpress or silence/knockout YAP1 using lentiviral transduction of constructs expressing shRNA/sgRNA or YAP1. We tested several tumor cell capabilities using well-established in vitro assays, including invasion and migration assays, and an in vivo brain metastasis (BM) model to determine the biological effects of YAP1/TEAD suppression at different stages of lung cancer progression. Dose-response assays were performed to determine IC50 of the TEAD inhibitor, verteporfin.

RESULTS
YAP overexpression enhances the proliferative phenotype in metastatic and BM cell lines but not in non-metastatic cells. However, YAP overexpression only increases the migration ability of BM cell lines such as LN001 and NCI-H1915 compared to the metastatic NCI-H1975 and non-metastatic lung cancer cells. Moreover, we showed the efficacy of the YAP1/TEAD inhibitor in patient-derived lung BM cells. Finally, our in vivo preliminary data showed YAP1 involvement in lung cancer cell colonization of the brain but not in sustaining brain metastasis growth.

CONCLUSIONS
Our findings showed YAP1 involvement in lung cancer cell colonization of the brain, suggesting YAP1 inhibition is a clinically actionable target for preventing lung cancer dissemination and providing a strong rationale to further evaluate the benefit of a YAP1/TEAD-targeted therapy in in vivo models of BM.
CSIG-16. A CX43-WNK1-C-MYC SIGNALING AXIS DRIVES GLIOBLASTOMA CANCER STEM CELL SURVIVAL
Authors: Mulkearns-Hubert Erin , Hajdari Nicole , Hong Ellen , Silver Daniel , Lathia Justin 
Published: November 2024

Abstract
Tumors represent a highly dynamic system that relies on coordinated signaling to drive growth and adapt to selective pressures, including those induced by anti-cancer therapies. Given the need for tumors to engage in rapid and coordinated cell-cell communication, mechanisms such as gap junction intracellular communication (GJIC) should be essential. However, the connexin proteins that make up gap junctions have traditionally been considered tumor suppressors based on the frequent loss of GJIC and lower connexin expression in tumor cells compared to non-neoplastic tissue. For this reason, connexin 43 (Cx43) has been proposed to suppress the growth of glioblastoma (GBM), the most common primary malignant brain tumor. However, recent data suggest that this tumor-suppressive effect is context dependent and that connexins can also function in a tumor-promoting role. Using next-generation sequencing techniques, we found Cx43 expressed at high levels in a panel of GBM patient-derived xenograft (PDX) CSCs and that these models rely on Cx43 for their survival and self-renewal. Mechanistically, depletion of Cx43 led to a dramatic loss of c-MYC expression through reduced phosphorylation of its upstream mediator WNK lysine-deficient protein kinase 1 (WNK1). Depletion of WNK1 phenocopied knockdown of Cx43 and reduced MYC protein and mRNA as well as tumor growth in vivo. Together, this work defines a novel signaling axis downstream of gap junction protein expression that promotes tumor growth and cancer stem cell phenotypes in GBM. Due to the difficulty in targeting both Cx43 and MYC, the identification of intermediate targetable signaling nodes may lead to improved therapies for patients with GBM.
CSIG-17. ADHESION GPCR BAI1/ADGRB1 CAN BLOCK IGF1R-MEDIATED GROWTH SIGNALLING, INCREASE RADIOSENSITIVITY AND AUGMENT SURVIVAL IN MEDULLOBLASTOMA
Authors: Yamamoto Takahiro , De Farias Virginea Araujo , Kuranaga Yuki , Zhu Dan , Parag Rashed R , Osuka Satoru , Van Meir Erwin G 
Published: November 2024

Abstract
Medulloblastoma (MB) is an aggressive pediatric brain tumors and increased knowledge about the disease mechanisms is needed to develop new therapeutic approaches. Brain-specific Angiogenesis Inhibitor 1 (BAI1/ADGRB1) is an adhesion GPCR receptor and tumor suppressor epigenetically silenced in MB. Our prior studies showed that BAI1 can bind the MDM2 E3 ubiquitin ligase and relocate it to the cell membrane, thereby preventing it from degrading p53 in the nucleus (Zhu et al, Cancer Cell, 2018). Whether other MDM2 targets are affected by this relocation that may be functionally important in MB development is unknown. We hypothesized that BAI1-mediated relocation of MDM2 might destabilize cell surface oncogenic receptors and found that BAI1 stimulates IGF1R poly-ubiquitination and degradation. Mechanistically, BAI1 fosters MDM2-IGF1R interaction through beta-arrestins, adaptor proteins connecting MDM2 to IGF1R. Epigenetic reactivation of BAI1 expression suppressed Stat3 and Akt signaling, and radio-sensitized MB cells, leading to significantly improved survival in orthotopic MB xenograft models in mice regardless of tumor p53 mutation status. These findings are important as they demonstrate that BAI1 has dual anti-tumor effects in MB through MDM2 membrane re-localization, stabilizing p53 and blocking IGF1R signaling. They further suggest that epigenetic targeting of BAI1 is a promising therapeutic approach for clinical translation.
CSIG-25. MAPK/ERK SIGNALING IN GLIOMAS MODULATES INTERFERON RESPONSES, PROMOTES TUMOR-MICROGLIA CROSSTALK, AND CONFERS SUSCEPTIBILITY TO ANTI-PD-1 AND ANTI-CTLA-4 IMMUNOTHERAPY
Authors: Kim Kwang-Soo , Zhang Junyi , Dmello Crismita , Grabis Elena , Arrieta Victor , Habashy Karl , Zhao Junfei , Duffy Joseph , Gould Andrew , Chen Li , Balyasnikova Irina , Canoll Peter , Sims Peter , Rabadan Raul , Lee-Chang Catalina , Heiland Dieter Henrik , Sonabend Adam 
Published: November 2024

Abstract
While immune checkpoint blockade (ICB) is not effective in unselected glioblastoma (GBM) patients, we previously established that MAPK/ERK signaling is associated with overall survival following anti-PD-1 and anti-CTLA-4 treatment in recurrent GBM. However, the causal relationship between MAPK/ERK signaling and susceptibility to ICB, as well as the mechanisms underlying this association, remain to be determined. We conducted in vivo kinome-wide CRISPR/Cas9 screenings in murine gliomas to identify key regulators of susceptibility to anti-PD-1 and CD8+ T-cell response and performed survival studies to validate the most relevant hits. Additionally, paired scRNA-seq with p-ERK staining, spatial transcriptomics, and ex-vivo slice culture of BRAFV600E mutant GBM tumors treated with BRAFi/MEKi were used to determine the causal relationship between MAPK signaling, tumor cell immunogenicity, and modulation of microglia phenotype. Our CRISPR/Cas9 screening results identified the MAPK pathway, particularly the RAF-MEK-ERK pathway, as the most critical modulator of glioma susceptibility to anti-tumoral immunity across all kinases. Survival studies showed that mice bearing high p-ERK gliomas exhibited prolonged survival with anti-PD-1 treatment, which was not seen when ERK phosphorylation diminished. MAPK activation in murine gliomas led to durable anti-tumoral immunity upon implant re-challenge, with memory T cell infiltration in long-term survivors. Elevated p-ERK in glioma cells was associated with interferon responses and antigen presentation. Moreover, in BRAFV600E human GBM cells with ERK1/2 knockout and in slice cultures of human BRAFV600E GBM tissue analyzed by spatial transcriptomics, we observed modulation of interferon responses by the MAPK/ERK pathway. Notably, in slice cultures from BRAFV600E mutant GBM, BRAFi/MEKi treatment disrupted the interaction between tumor cells and tumor-associated macrophages/microglia. In conclusion, the MAPK/ERK pathway is a critical driver of GBM susceptibility to anti-tumoral immunity, modulating the interferon responses and antigen-presenting machinery in glioma cells, as well as tumor cell interaction with the microenvironment.
CSIG-27. GLIOBLASTOMA CELL STATE PLASTICITY AND THERAPEUTIC RESISTANCE IS MEDIATED BY BRD2
Authors: Vadla Raghavendra , Taylor Brett , Miki Shunichiro , Miyake Yohei , Kawauchi Daisuke , Furnari Frank 
Published: November 2024

Abstract
GBM is a highly aggressive primary brain tumor in adults, notable for its heterogeneity, high recurrence rates, and increased resistance to therapy. Multi-omics analyses have consistently identified three distinct transcriptionally defined cell states – proneural (PN), classical (CL), and mesenchymal (MES) – in IDH-wildtype GBM, with high plasticity among these states in response to diverse stimuli. Transition of GBM cells to a MES cell state is particularly associated with high invasiveness, resistance to therapy, and recurrence. However, the underlying mechanisms driving the MES transition remain poorly understood. In this study we identified the PTEN/NF-kB/BRD2 pathway as key driver of the MES transition, with BRD2 acting as a crucial epigenetic modulator for cell state transitions in GBM. We demonstrate that PTEN plays a critical role in regulating the chromatin binding of BRD2, BRD4 and p65/RelA. Additionally, acetylation of RelA at lysine 310 is required for BRD2 localization to the promoters of MES genes, which is essential for their expression. Loss of BRD2 leads to transition of GBM cells from MES to PN cell state and displayed enhanced sensitivity to ionizing radiation (IR). Further, bromo domains (BDs) of BRD2 are important for MES transition, as mutations in these domains resulted in transitioning of GBM cells from MES to other cell states. Furthermore, we show that BD2-specific BET inhibitors displace BRD2 from MES gene promoters, abrogate MES transition, and enhance GBM sensitivity to IR. Using a brain-penetrant BD2 inhibitor, we effectively reduced GBM cell invasion and tumor-associated microglia/macrophage (TAM) abundance in orthotopic xenograft models. These findings establish BRD2 as a key regulator of MES transition and therapeutic resistance in GBM models, paving the way for the use of bromodomain-specific BET inhibitors in targeting MES GBM.
RADT-05. VASCULAR OVERLAP PROVIDES PROTECTION FROM GAMMA-KNIFE-INDUCED RADIATION NECROSIS IN A METASTATIC BRAIN TUMOR COHORT
Authors: Berke Chandler , Knott Maxon , Spatz Jordan , Silva Michael , Khalafallah Adham , Valderrama Alessandro , Diwanji Tejan , Komotar Ricardo , Ivan Michael , Rich Benjamin , Benjamin Carolina 
Published: November 2024

Abstract

INTRODUCTION
Radiation necrosis (RN) is a long-term complication of Gamma-Knife (GK) Radiosurgery, an established treatment for metastatic brain tumors. Few dosimetric parameters have shown to predict RN, including tumor target volume, treatment dose, and V12 Gy (volume of normal brain receiving 12 Gy). Vascularity has yet to be explored as an independent predictor of RN.

OBJECTIVE
To evaluate the role of vascular overlap in GK-induced RN.

METHODS
All metastatic brain tumor patients treated with GK between 2014-2019 were retrospectively screened for post-treatment radiographic RN. Vascular overlap, defined by the MCA-ACA and MCA-PCA border regions, was determined by two blinded neurosurgeons and one radiation oncologist. Multivariate logistic regression analysis was performed to determine factors predictive of RN using variables determined significant by univariate analysis and clinical relevance. Covariates included V12 as a binary variable (≥8 vs. &lt;8 cm3), vascular overlap, supratentorial location, and eloquent location.

RESULTS
6% (20/321) of all metastatic brain tumor patients developed RN and were included for analysis, with the final cohort being 60% (12/20) female with a mean age of 59 years, comprising 77 lesions. V12 (≥8 cm3) showed a significant increase in risk of developing RN [OR = 8.18; (coef, 95% CI: 2.10 (0.49, 3.72), p=0.011)]. Conversely, vascular overlap showed a protective effect against RN [OR = 0.23 (-1.49 (-2.79, -0.19), p=0.024)], with a lower rate of RN in areas of vascular overlap (10%) than non-vascular overlap (26%). Neither supratentorial location [OR = 3.31 (1.20 (-0.76, 3.16), p=0.231)] nor location within eloquent brain [OR = 0.96 (-0.04 (-1.48, 1.39), p=0.95)] showed significance.

CONCLUSION
For the first time, we show that patients with metastatic brain lesions in anatomical regions of vascular overlap treated with GK are less likely to develop RN. Future work should validate these findings with the goal of optimizing radiation dosing to mitigate RN incidence and recurrence rates.
RADT-06. IDENTIFICATION OF NEW RADIATION RESPONSE PREDICTOR GENES FOR GLIOBLASTOMACRUCIAL CONTRIBUTION OF THE LUNATIC FRINGE GENE (LFNG)
Authors: Naim Asmaa , baddou abdallah 
Published: November 2024

Abstract

Glioblastoma (GBM) is adults’ most common aggressive primary intracranial tumor. The current standard of care involves maximal safe surgery followed by radiochemotherapy.

OBJECTIVE
our study was to identify genes that predict response to radiochemotherapy.

MATERIALS AND METHODS
We collected molecular and clinical data, including primary glioma mRNA expression, from two international online databases - TCGA and CCGA. A total of 76 cases were examined, with 41 patients in the TCGA cohort and 35 in the CCGA cohort. The patients were divided into two groups before assessing the data. Group 1 included patients who were alive at the time of the analysis, and Group 2 included patients who had passed away. Then, we performed a single-center Moroccan transcriptomic study involving 28 cases to assess the impact of the individualized gene in our environment.

RESULTS
The following genes, namely SRPX, S100A16, LFNG, CD5, CMBL, and TCTN2, are among the top genes co-overexpressed in TCGA and CGGA patients. We conducted a multivariate COX survival test, taking into account known prognostic clinical parameters, and found that the LFNG gene is the only marker of poor prognosis independent of other clinical markers in TCGA and CGGA patients treated with radiotherapy. Our results indicate that patients who overexpress LFNG have elevated IFNg levels and low granzyme B levels, while the levels of perforin and granzyme A remain unaffected by LFNG variation. Furthermore, our results demonstrate positive correlations between LFNG gene expression and four immune checkpoints (PD1, PDL1, CTLA4, and VISTA), but negative correlations only with TIM3.

CONCLUSION
Our findings suggest that LFNG could serve as a useful biomarker for identifying patients with poor prognosis and that LFNG expression may be associated with specific immune checkpoint expression patterns. These results have important implications for the development of new therapeutic approaches in the treatment of TCGA and CGGA patients.