bluuebunny/crossref_metadata_2025_split huggingface dataset:
CNSC-23. CROSSTALK BETWEEN STROKE AND GLIOMA: ISCHEMIA-INDUCED NEURONAL ACTIVATION ON GLIOMA INFILTRATION
Authors: Madamba Christine , Ye Qi , Lee Hyun Kyoung 
Published: November 2024

Abstract
Glioblastoma (GBM) is an aggressive primary brain tumor associated with dismal survival rates. GBM is difficult to treat due to its ability to invade neighboring brain regions, rendering complete surgical resection nearly impossible. Throughout tumor progression, several pathological changes occur in the tumor microenvironment (TME) including increased neuronal hyperactivity. Interestingly, these pathological features also occur in stroke, a leading global cause of death and disease burden. Clinical evidence from large cohort studies reveals a 10% risk of brain tumor development in stroke patients, suggesting a link between these two diseases. However, the intricacies of their association and whether stroke poses a long-term risk for GBM is unclear. To investigate this, we have developed innovative stroke-glioma mouse models to recapitulate and delineate the interrelationship between these two diseases. Our data using these models indicate a substantial increase in tumor growth and infiltration towards the infarct using both human GBM-patient derived glioma cells in immunodeficient mice as well as in immunocompetent de novo mouse GBM. Further, spatial manipulation of stroke and glioma induction revealed that glioma cells preferentially invade the contralateral hemisphere towards the stroke lesion compared to control. This suggests stroke-induced changes may trigger glioma cell infiltration. Histological analysis of the TME shows increased neuronal activity specifically excitatory neuron synaptic marker expression in the leading edge of glioma post-stroke compared to control. Overall, stroke induction may promote tumor growth and infiltration by modulating the TME through increasing excitatory neuronal activation. Together, this study aims to deepen our understanding of the influence of stroke on gliomas, paving the way for invaluable insights essential for identifying at-risk patients and the development of potential treatments for affected patients.
CNSC-34. SURGICAL INTERVENTION ASSOCIATION WITH THE DEVELOPMENT OF SUBSEQUENT DISSEMINATION IN CHILDHOOD DIFFUSE INTRINSIC PONTINE GLIOMAS (DIPG)
Authors: Bashir Shoaib , Lai Mingyao , Cai Linbo 
Published: November 2024

Abstract

BACKGROUND
Diffuse intrinsic pontine glioma (DIPG) is one of the most aggressive pediatric central nervous system tumors, and currently, there are no curative treatment options available. With the increasing application of molecular diagnostics, more and more DIPG patients are recommended to undergo surgery; however, its correlation with dissemination needs to be better understood. Hence, we conducted this cohort to analyze the predictors of subsequent metastasis in pediatric DIPGs.

METHODS
The final analysis included 142 pediatric (age ≤ 12) DIPG patients treated at Sanjiu Brain Hospital between January 2017 and September 2023. The data were retrospectively collected following the initial diagnosis. Patients were followed up for 6 months. The primary endpoint was the occurrence of subsequent metastasis. Univariable and multivariable logistic regression analyses were utilized to identify statistically significant predictors of subsequent dissemination. All statistical assessments were two-tailed, and only P &lt; 0.05 was deemed to be statistically significant.

RESULTS
Among 142 patients, 14(9.9%) developed metastasis within the follow-up time. There were 77(54.2%) males and 65(45.8%) females. The median age was 7 years (ranging 1 - 12 years). The overall cohort demonstrated that surgery was the only predictor of dissemination both in univariable (OR 4.567, 95%CI 1.351 – 20.901, P = 0.024) and multivariable (OR 5.501, 95%CI 1.560 – 26.105, P = 0.014) analyses. However, subgroup analysis involving patients who received surgical intervention showed that biopsy was not superior nor inferior to resection in terms of relative risk for subsequent dissemination (16.7% vs. 15.8%).

CONCLUSION
Surgical intervention increases the relative risk of dissemination occurrence to four times more than those who did not receive surgery. Surgical intervention is crucial given the potential of molecular analysis leading to improved therapeutic options. Nonetheless, patients should be informed about the risks associated with surgery, including subsequent metastasis.
CNSC-35. TEMOZOLOMIDE POTENTIALLY POSTPONES THE DEVELOPMENT OF SUBSEQUENT METASTASES IN PEDIATRIC DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) PATIENTS
Authors: Bashir Shoaib , Lai Mingyao , Cai Linbo 
Published: November 2024

Abstract

OBJECTIVE
Surgical intervention is thought to increase the likelihood of subsequent dissemination in diffuse intrinsic pontine glioma (DIPG) patients. However, there is no study evaluating the factors influencing the timing of metastasis development. Hence, the present analysis was conducted to shed light on factors associated with subsequent dissemination timing.

METHODS
This analysis included 28 pediatric (age≤12) DIPG cases with metastasis treated at Sanjiu Brain Hospital between June 1, 2017 and June 30, 2023. The clinical data were retrospectively collected following the initial diagnosis. The diagnosis was established by typical imaging features of DIPG. The same three radiologists analyzed the imaging data independently. Time to subsequent metastasis was estimated using Kaplan–Meier analysis, and a log-rank test evaluated the differences between groups.

RESULTS
Of 28 patients, 13 (46.4%) were males and 15 were females. 23 (82.1%) underwent surgical intervention, while 5 (17.9%) did not receive surgery. The patients’ median age was 7 years (2-12 yrs.). The Kaplan-Meier method showed that the median time to metastasis was 5.8 months (95%CI 4.2-9.1). The log-rank test demonstrated that adjuvant temozolomide was the only variable that could significantly delay metastasis in the pediatric DIPG population (P=0.03). The median time to metastasis from the day of initial diagnosis for those who received adjuvant temozolomide was 6.8 months (95%CI 5-10.7) vs. 3 months for those who did not receive adjuvant temozolomide (95%CI 2.3-NA). Sex, age, surgical intervention, and concurrent irradiation and temozolomide were not associated with metastasis timing.

CONCLUSION
Adjuvant temozolomide administration might benefit DIPG patients by delaying metastasis, especially in those who are at higher risk for subsequent metastasis, such as those who underwent surgical intervention. However, prospective studies are warranted to confirm these results.
CNSC-36. REGULATION OF CELL FATE IN PAEDIATRIC HIGH-GRADE GLIOMA BY THE HOMEOBOX TRANSCRIPTION FACTOR DLX2
Authors: Furst Liam , Roussel Enola , Leung Ryan , George Ankita , Li Jason , Best Sarah , Whittle James , Cain Jason , Firestein Ron , Faux Maree , Eisenstat David 
Published: November 2024

Abstract
Paediatric high-grade gliomas (pHGG) are nearly uniformly fatal cancers that arise predominantly in children and adolescents and encompass Diffuse Midline Glioma (DMG) and Diffuse Hemispheric Glioma (DHG). Most patients harbour mutations in histone variants H3.1 or H3.3, resulting in global epigenetic dysregulation and a stalled oligodendroglial progenitor (OPC) or GABAergic interneuron progenitor (IP) fate for DMG and DHG, respectively. DLX2, a homeobox transcription factor, represses OPC fate and promotes IP cell fate and migration during early neurogenesis. Our lab has shown that Dlx2 binds to and regulates the promoters of Gad1/Gad2, as well as early (Olig2, Nkx2.2) and late (Myt1, Plp1) genes required for OPC differentiation in vivo. Co-expression of Dlx2 with these target sequences reduces reporter gene expression in vitro and Dlx1/2 double knockout mice exhibit increased expression of these OPC markers in vivo. Transient overexpression of a Dlx2-GFP construct in murine DMG cells led to significant IP marker increase (Gad1/2), decrease of OPC markers (Olig2, Nkx2.2) and global restoration of H3K27me3. Additionally, decreased proliferation, colony growth, invasion and migration were observed in vitro. To translate these findings in human pHGG, analysis of a bulk RNA-seq database of 62 patient-derived pHGG cell lines revealed an inverse relationship between DLX2 and OLIG2. DLX2 was knocked out of DLX2high/OLIG2low DHG cell lines using CRISPR-Cas9, and overexpressed in DLX2low/OLIG2high DMG cell lines using a DLX2-mCherry overexpression construct. Evaluation of cell fate markers and epigenetic marks will be presented. Changes in migration, invasion, and proliferation in vitro will also be presented, in addition to changes in tumour growth using a neonatal xenograft murine model in vivo. Manipulation of DLX2 in pHGG provides a model for investigating the link between the factors that control cell fate decisions in the developing brain and the aberrant differentiation state in pHGG.
CNSC-38. INFLUENCE OF AGE, IMMUNOREGULATORY IDO, AND IMMUNOTHERAPY ON THE MICROBIOME IN MICE WITH AN EXPERIMENTAL BRAIN TUMOR
Authors: Zhai Lijie , Shrestha Akriti , Lauing Kristen , Penco-Campillo Manon , Ojo Oluwatomilayo , Bommi Prashant , Koch Taylor , Hatton Kyla , McCusker Robert , Anderson Douglas , Prabhu Vikram , Thakkar Jigisha , Allen Jacob , Wainwright Derek 
Published: November 2024

Abstract

OBJECTIVE
This study aimed to determine how IDO and subject age impact the gut microbiome and microbial metabolites during immunotherapy for glioblastoma (GBM).

METHODS
Serum and colon contents were collected from young 16-20- or older adult 92-118-week-old wild-type (WT; C57BL/6), IDO knockout (IDOKO), and IDO enzyme null (H350A) mice analyzed for 16S rRNA gut microbiome composition and microbial-derived aromatic amino acid metabolites via LC/MS/MS. Fecal samples from young 7-8 or older adult 81-85 week-old WT mice with intracranial GL261 brain tumors treated with or without brain radiation (RT) and PD-1 mAb were also analyzed.

RESULTS
Young and old IDOKO and H350A mice demonstrated a unique gut microbiome signature with an elevated abundance of Bifidobacterium and Helicobacter (p&lt;0.05) and a reduced abundance of Ventriosum and Sireaum compared to WT mice (p&lt;0.001). Prevotellaceae, Muribaculum, Alistipes, Enterohabdus, Clostridia, and Akkermansia were different in IDOKO and H350A mice compared to WT - but only in old mice. Serum aryl-lactates including phenyllactate, indolelacatate, and 4-hydroxyphenyllactate were increased in IDOKO mice compared to WT and H350A mice (p&lt;0.001) – again, only in old mice. Older adult WT mice with GL261 showed lower fecal aryl-lactates compared to younger counterparts. Treatment with RT + PD-1 mAb decreased phenyllactate levels in old but not young mice with GL261 (p&lt;0.05).

CONCLUSIONS
There are IDO enzyme- and non-enzyme-dependent effects on gut microbiota composition and bioactive microbial aromatic amino acid metabolites. These data warrant further investigation into how microbial metabolism affects immunotherapy efficacy and brain tumor survival across the lifespan.
CNSC-47. SENOLYTICS ERADICATE SENESCENT MICROGLIA IN THE BRAIN PARENCHYMA AND IMPROVE SURVIVAL IN OLDER ADULT MICE WITH GLIOBLASTOMA
Authors: Penco-Campillo Manon , Zhai Lijie , Bommi Prashant , Ojo Patience , Lauing Kristen L , Sanchez-Gomez Pilar , Anderson Douglas , Prabhu Vikram , Thakkar Jigisha , Lukas Rimas V , Wainwright Derek A 
Published: November 2024

Abstract

BACKGROUND
Glioblastoma (GBM) is the most common aggressive primary malignant brain tumor in adults with a poor median survival rate. Despite the aggressive standard of care treatment combining surgical resection, chemo-, and radio-therapy, the median overall survival (OS) is only ~15-18 months. Progressively increasing subject age is inversely associated with GBM patient OS such that older adults tend to have significantly worse survival outcomes compared to younger counterparts. Senescent cells accumulate in the body during progressive aging and contribute to worse outcomes in older adult mice with GBM. Senolytics are pharmacologics that cause senescent cells to undergo cell death.

OBJECTIVE
To comprehensively profile the treatment effect of senolytics combined with or without immunotherapy in mice with GBM across the lifespan.

METHODS
Young 7-9- and older adult 97-104-week-old wild-type (WT; C57BL/6) and 110-130-week-old INK-ATTAC mice with or without intracranial SB28 cells were treated with or without brain radiation (RT), PD-1 mAb, and an IDO enzyme inhibitor with the senolytics, dasatinib + quercetin, or the AP compound that induces p16INK4A+ senescent cell death in INK-ATTAC mice (n=5/group). The quantification of beta-galactosidase positive cells by flow cytometry was performed on brain-resident neurons, astrocytes, oligodendrocytes, microglia, as well as dendritic cells, macrophages, neutrophils, T cells in the tumor and non-tumor bulk mass. Overall survival was also evaluated.

RESULTS
Senolytics or AP compound treatment both decrease beta-galactosidase positive microglia in the older adult brain with GBM (p&lt;0.05). Combining radio- and immuno-therapy with senolytics improves overall survival of older adult mice with intracranial GBM (p&lt;0.05).

CONCLUSIONS
Our ongoing work aims to understand how senescent microglia affect neuronal health and function in the older adult brain with GBM.

KEYWORDS
Glioma, senescence, senolytic.
CNSC-52. OLIGODENDROGLIOMA SPATIAL TRANSCRIPTOMIC SEQUENCING REVEALS THERAPY-DEPENDENT EVOLUTION OVER TIME
Authors: Mirchia Kanish , Young Jacob , Nguyen Minh , Vasudevan Harish , de Groot John , Raleigh David 
Published: November 2024

Abstract
Oligodendroglioma evolution is incompletely understood. Here we analyze serial oligodendroglioma samples to define genomic and cellular mechanisms underlying treatment resistance. RNA sequencing was performed on 53,406 spatial transcriptomes from 31 oligodendrogliomas (IDH mutant, 1p/19q-codeleted) that were resected from 16 patients. There were 15 CNS WHO grade 2 and 16 grade 3 oligodendrogliomas, which were stratified for temporal progression across grades (n=5 grade 2 to 2, n=5 grade 2 to 3, n=6 grade 3 to 3) and treatments between serial resections (n=2 TMZ/RT, n=2 TMZ, n=1 mTOR inhibition, n=1 IDH inhibition, n=10 surgical monotherapy). Spatial transcriptomic clusters were defined using cell signature gene sets, cell cycle analysis, differentially expressed marker genes, immunohistochemistry, spatial copy number alterations (CNAs), and deconvolution of 18,628 oligodendroglioma single-cell transcriptomes from 16 independent patients. Specificity was tested using immunofluorescence on independent oligodendrogliomas that did not recur after surgical monotherapy (n=8 samples, median follow-up 8.4 years) and spatial transcriptomic sequencing on 8 matched-paired astrocytomas from 4 patients. Integrated uniform manifold approximation and projection revealed a proneural/NPC-like cluster that was enriched in grade 3 oligodendroglioma samples and represented the starting point in oligodendroglioma lineage differentiation using RNA velocity, Monocle, and subclonal spatiotemporal CNA evolution. Comparison across treatment regimens showed (1) enrichment of the proneural/NPC-like cluster in recurrent versus primary tumors that were treated with surgical monotherapy, (2) enrichment of a proneural/OPC-like cluster and depletion of an oligodendrocyte-like cluster after TMZ/RT, (3) enrichment of proneural/NPC-like and immediate-early response clusters after TMZ/RT, (4) enrichment of the oligodendrocyte-like cluster following mTOR inhibition, and (5) enrichment of cancer associated fibroblasts (CAFs) following IDH inhibition. These data show the spatiotemporal landscape of oligodendroglioma is associated with branched lineage differentiation that is modified by postoperative therapy, and suggest that therapy-dependent druggable dependencies may exist to treat oligodendrogliomas that are resistant to standard interventions.
CNSC-55. UNCOVERING THE ROLE OF COLLAGEN EXTRACELLULAR MATRIX IN GLIOBLASTOMA BRAIN MICROENVIRONMENT TRANSFORMATION
Authors: Hashemi Melika , Selvam Durgadevi , Hale Reid J , Shockley Katelynn , Zhyrgalbekovna Ailin , Comba Andrea 
Published: November 2024

Abstract
Glioblastoma (GBM) is a highly malignant brain tumor characterized by diffuse infiltration and significant heterogeneity, without effective treatment. Mesenchymal-like (MES) glioma cells drive tumor aggression by promoting brain invasion and tumor microenvironment remodeling. Previous spatial transcriptomic analyses identified Collagen, particularly COL1A, as a key extracellular matrix (ECM) component, enriched in MES areas termed oncostreams. Depletion of COL1A1 disrupted oncostreams, influencing the tumor microenvironment to support cell survival, and migration. Reactive astrocytes and macrophages, essential components of the brain microenvironment, impact glioma progression. However, the interplay between glioma-secreted collagen and the brain microenvironment remains poorly understood. To elucidate this, we generated orthotopic mouse glioma models with high-collagen (NPD) and low-collagen (NPDshCol1A1). Our data revealed that downregulation of COL1A1 in glioma cells alters the abundance and spatial distribution of reactive astrocytes and macrophages/microglia. Immunofluorescence and flow cytometry analysis showed that tumors with low-collagen had decreased GFAP+ reactive astrocyte cells at the invasive edge and perivascular niche compared to high-collagen gliomas. Moreover, our results shows that high collagen levels may activate astrocytes through distant communication, as evidenced by the higher presence of reactive astrocytes in the contralateral cortex of NPD tumors. However, low-collagen tumors exhibited an increase in astrocytes (GFAP+) in the tumor core. Furthermore, high-collagen gliomas demonstrated increased macrophage infiltration, promoting an immunosuppressive environment. Using multiplex immunohistochemistry assays, we observed that reactive astrocytes along the invasive tumor edge were associated with glioma cells expressing elevated levels of COL1A1 and TGF-β ligand. In summary, our results show that glioma cell-expressed COL1A1 promotes the activation of peritumoral and perivascular brain-resident astrocytes and macrophages. The interactions of reactive astrocyte with glioma cells enriched in collagen form a feedback loop that enhances tumor invasion and vascular proliferation, suggesting that targeting the ECM-astrocyte interactions could disrupt these processes and offer a therapeutic avenue for GBM.
CNSC-57. THE ROLE OF NEURON-TO-GLIOMA SYNAPTIC COMMUNICATION IN THERAPEUTIC RESISTANCE
Authors: Tetzlaff Svenja K , Reyhan Ekin , Bengtson C Peter , Layer Nikolas , Faymonville Anton J , Heuer Alina , Venkataramani Varun 
Published: November 2024

Abstract
Glioblastomas, primary brain tumors known for their extensive brain colonization and high therapeutic resistance, pose significant treatment challenges. Recent research has revealed that glioblastoma cells can form functional multicellular networks both with themselves, surrounding astrocytes and neurons. However, the investigation of the glioblastoma neuronal connectome has been limited by a lack of suitable methodologies. In this study, we utilized an adapted rabies-based retrograde tracing approach to characterize tumor-connected neurons and examine the neuronal connectome of the tumor in the context of therapy resistance. Our initial findings demonstrated that radiotherapy induces hyperexcitability in tumor-connected neurons, as shown by patch-clamp electrophysiology. This hyperexcitability was associated with an increase in neuron-tumor connectivity post-irradiation. To mitigate this increased neuronal input to therapy-resistant glioblastoma cells, we combined radiotherapy with the anti-epileptic drug perampanel. This combination therapy, which inhibits overall neuronal activity while delivering tumor cell-toxic photon irradiation, proved significantly more effective in reducing the number of therapy-resistant tumor cells. In summary, we employed a novel methodology to investigate the role of the neuronal tumor connectome in therapeutic resistance, identifying tumor-connected neurons as a potential target for improving glioblastoma treatment.
CNSC-61. NEURONAL-ACTIVITY DEPENDENT MECHANISMS OF SMALL CELL LUNG CANCER PATHOGENESIS
Authors: Savchuk Solomiia , Wang Wengang , Gentry Kaylee , Carleton Elana , Biagi Carlos , Yalçın Belgin , Ni Lijun , Farnsworth Hannah , Davis Rachel , Liu Yin , Acosta-Alvarez Lehi , Hartmann Griffin , Pavarino Elisa , LaBelle Jenna , Toland Angus , Woo Pamelyn , Qu Fangfei , Filbin Mariella , Krasnow Mark , Ligon Keith , Sage Julien , Sabatini Bernardo , Monje Michelle , Venkatesh Humsa 
Published: November 2024

Abstract
Neural activity is increasingly recognized as a crucial regulator of cancer growth. In the brain, neuronal activity robustly influences glioma growth both through paracrine mechanisms and through electrochemical integration of malignant cells into neural circuitry via neuron-to-glioma synapses. Outside of the CNS, innervation of tumors such as prostate, breast, pancreatic, and gastrointestinal cancers by peripheral nerves similarly regulates cancer progression. However, the extent to which the nervous system regulates lung cancer progression, either in the lung or when metastatic to the brain, is less well understood. Small cell lung cancer (SCLC) is a lethal high-grade neuroendocrine tumor that exhibits a strong propensity to metastasize to the brain. Here we demonstrate that SCLC cells in the brain co-opt neuronal activity-regulated mechanisms to stimulate growth and progression. With in vivo optogenetic stimulation, we show that glutamatergic and GABAergic cortical neuronal activity each drive proliferation of SCLC through both paracrine and synaptic neuron-cancer interactions. In the brain, SCLC cells form bona fide neuron-to-SCLC synapses evident on immunoelectron microscopy for the first time for non-brain derived malignancy. Using electrophysiology and two-photon calcium imaging, we find that SCLC cells exhibit depolarizing currents with consequent calcium transients in response to neuronal activity. SCLC cell membrane depolarization is sufficient to promote the growth of intracranial tumors. We also demonstrate reciprocal effects of SCLC on neurons, manifesting as increased neuronal synaptogenesis and elevated field potentials in regions of the tumor. Finally, in the lung, vagus nerve transection markedly inhibits primary lung tumor formation and development and awards survival benefit in spontaneous genetic SCLC model, highlighting a critical role for innervation in overall SCLC growth. Taken together, these studies illustrate that neuronal activity plays a crucial role in dictating SCLC pathogenesis in both the lung and the brain.