bluuebunny/crossref_metadata_2025_split huggingface dataset:
STEM-24. SINGLE-CELL ATLAS OF HUMAN FETAL CEREBELLUM DECODING MEDULLOBLASTOMA ORIGIN AND ONCOGENESIS
Authors: Luo Zaili , Lu Richard 
Published: November 2022

Abstract
Medulloblastomas (MBs) are the most common malignant childhood brain tumors, yet the origin of the most aggressive subgroup-3 form remains elusive, impeding development of effective targeted treatment strategies. Previous cell-type analyses of mouse cerebella or human counterparts from frozen tissue nuclei have not fully defined the compositional heterogeneity of MBs. Here, we undertook an unprecedented single-cell profiling of freshly-isolated human fetal cerebella at different developmental stages to establish a reference map for delineating the hierarchical cellular states in MBs. We identified a unique transitional cerebellar progenitor connecting neural stem cells to neuronal lineages in human fetal cerebella. Intersectional analysis revealed that the transitional progenitors were enriched in aggressive MB subgroups, including group-3 and metastatic tumors. Integrated single-cell multi-omic profiling revealed unique regulatory networks in the transitional progenitor populations, including transcriptional determinants HNRNPH1 and SOX11, which are correlated with clinical prognosis in aggressive group-3 MBs. Genomic profiling and Hi-C analyses identified de novo long-range chromatin loops juxtaposing HNRNPH1/SOX11-targeted super-enhancers to cis-regulatory elements of MYC, an oncogenic driver for group-3 MBs. Targeting the transitional progenitor regulators inhibited MYC expression and MYC-driven group-3 MB growth. Together, our integrated single-cell atlases of human fetal cerebella and MBs reveal important cell populations predisposed to transformation and regulatory circuitries underlying tumor cell state evolution and oncogenesis, highlighting hitherto unrecognized transitional progenitor intermediates predictive of disease prognosis and potential therapeutic vulnerabilities.
STEM-28. THE ROLE OF LONP1 IN DRIVING ENHANCED PMT IN THE 'LEADING EDGE' NICHE IN GLIOBLASTOMA
Authors: Lepe Javier , Douglas Chris , Di Kaijun , Nandwana Nitesh , Das Bhaskar , Bota Daniela 
Published: November 2022

Abstract
Glioblastoma (GBM), a high grade brain tumor, possesses poor overall survival with less than 5% surviving past five years. Previously, the TCGA classifications for GBM have included the mesenchymal, proneural, classical and neural subtypes with their own respective expression profiles and survival. Recent omics analysis has revealed other key aspects of GBM pathology, including intratumoral heterogeneity spanning all subtypes and enhanced stemness and treatment resistance and other hallmarks of proneural mesenchymal transition (PMT) following treatment with first-line standard of care treatment with radiation therapy and temozolomide (TMZ). Invading glioma stem cells (GSC) with high Nestin and hypoxia-inducible factor 1 alpha (HIF-1α) expression have been theorized to contribute to recurrence. HIF-1α acts as a master regulator driving increased stemness, invasiveness and angiogenesis. Interestingly, HIF-1α and nuclear respiratory factor-2 both upregulate Lon peptidase 1 (LonP1) in response to increased hypoxia or reactive oxygen species (ROS) production. LonP1 has been shown to drive increased metastasis, tumor growth and epithelial-mesenchymal transition (EMT), an analog of PMT, in colon cancer, melanoma and other cancer types. In a recently elucidated GBM organoid model, we present new findings demonstrating the importance of LonP1 in driving enhanced, transient PMT near the ‘invading edge’. This includes the enhanced expression of several key drivers of PMT and phenotypic hallmarks, such as increased invasiveness, proliferation and poorer survival.
CSIG-01. EGFR AND AXL RECEPTOR TYROSINE KINASES DRIVE ONCOGENESIS BY LZTR1 MUTATION
Authors: Ko Aram , Hasanain Mohammad , Oh Young Taek , D'Angelo Fulvio , Sommer Danika , Frangaj Brulinda , Tran Suzanne , Bielle Franck , Pollo Bianca , Paterra Rosina , Mokhtari Karima , Soni Rajesh , Peyre Matthieu , Eoli Marica , Kalamarides Michel , Sanson Marc , Iavarone Antonio , Lasorella Anna 
Published: November 2022

Abstract
LZTR1, the substrate-specific adaptor of a CUL3-dependent ubiquitin ligase is among the most frequently mutated ubiquitin ligase coding gene in syndromic and sporadic human cancers including glioblastoma multiforme, in which approximately 27% of cases harbor inactivating mutations and copy number loss. However, both the identity of the protein substrates targeted by LZTR1-mediated ubiquitylation and the biological contexts regulated by specific LZTR1-substrate(s) interactions remain uncertain. Here, we combined biochemical and genetic studies to identify LZTR1 substrates and interrogated their tumor-driving function in the context of LZTR1 loss-of-function mutations and in a new conditional Lztr1 knockout mouse. Multiple screens converged on the receptor tyrosine kinases EGFR and AXL as LZTR1 interactors targeted for ubiquitin-dependent degradation in the lysosome by LZTR1-CUL3 complexes. Pathogenic mutations affecting LZTR1 failed to promote degradation of EGFR and AXL in human tumors. Mice harboring conditional deletion of the LZTR1 gene combined with loss of CDKN2A in the neural progenitor compartment generated peripheral nervous system tumors including schwannoma like and malignant peripheral nervous system tumors (MPNST). Tumors from the LZTR1-mutant mouse model accumulated very high levels of EGFR and AXL and exhibited potent and specific vulnerability to the combinatorial inhibition of EGFR and AXL kinases. These findings explain the mechanism of tumorigenesis associated with LZTR1 inactivation and offer a therapeutic strategy to patients affected by tumors carrying mutations of LZTR1.
CSIG-11. HYPOXIA SIGNALING IN ACVR1-MUTANT DIFFUSE INTRINSIC PONTINE GLIOMA
Authors: Johansson Elinn , Pietras Alexander 
Published: November 2022

Abstract
Diffuse intrinsic pontine glioma (DIPG) is a devastating glial tumor of the brainstem primary occurring in the pediatric population. The majority of DIPG tumors (60-80%) carry lysine- to methionine point mutation in histone H3, resulting in a global reduction of H3K27 trimethylation and subsequently a unique epigenetic landscape. Moreover, a large subset of the DIPG tumors carry activating mutations in ACVR1 – the gene encoding for the BMP receptor ALK2, suggesting an oncogenic role of signaling from this receptor. Importantly potential mechanisms of ACVR1-driven oncogenesis, remain poorly understood. Similar ACVR1 mutations have been described in the rare disorder Fibrodysplasia Ossificans Progressiva (FOP), and evidence from FOP models have suggested several links between hypoxia signaling, BMP signaling, and FOP pathogenesis thus opening up for evaluation of hypoxia signaling as oncogenic effector in ACVR1mutant DIPG. Using cultured DIPG cells and adult glioma cells respectively we have tested the activity of the hypoxia pathway using a hypoxia-responsive elements (HRE)-luciferase reporter assay. Intriguingly, DIPG but not glioma cells overexpressing a mutant ACVR1 construct significantly elevated hypoxia signaling at hypoxia. Similar trends are seen when assaying neuronal stem cell cultures harboring Histone 3.1 mutations along with activated ACVR1/ALK2 signaling. Furthermore, BMP ligand stimulation resulted in a dose-dependent increase of hypoxia signaling in DIPG cells. Through querying clinical gene expression data, we found elevated hypoxia signature scores in pediatric gliomas with mutant ACVR1 as compared to those with wildtype ACVR1. Finally, ACVR1 mutations frequently co-occur with Histone 3.3 and 3.1 mutations, and the hypoxia signature score was significantly higher than baseline only in tumors also harboring these Histone 3.3 or 3.1 mutations. Together, our data suggest that hypoxia signaling is elevated downstream of ACVR1 specifically in pediatric gliomas and prompts for evaluation of hypoxia signaling as potential therapeutical target in DIPG.
CSIG-25. DIFFERENTIAL YAP ACTIVITY IN HUMAN GLIOBLASTOMA TUMORSPHERES AS A POTENTIAL BIOMARKER
Authors: Kim Eui Hyun , Kang Seok-Gu 
Published: November 2022

Abstract

BACKGROUND
Hippo/YAP signaling pathway has emerged as an important driver of GBM. However, the clinical significance and expression correlation of YAP in GBM is still unknown. The purpose of this study is to elucidate the regulatory functions of YAP in response to tumorspheres (TS) in GBM. Material and

METHODS
In GBM-tumorspheres (TS), mRNA levels of Yap1 and TAZ were determined by RNA-Seq, and nuclear YAP1 expression level and its correlation with tumor aggressiveness were assessed through nucleus cytosolic fractionation, quantitative confocal microscopy, western blot, and TEAD4 reporter assay. Cell proliferation, stemness, and invasive properties were also measured using YAP siRNA and its inhibitor Verteporfin to reveal the effect of YAP on glioma progression. In orthotopic xenograft models, the inhibition of YAP function were tested.

RESULTS
All GBM-TS exhibited various phosphorylation states of YAP but no significant differences regarding the expression of YAP. Among them, TS15-88 cell line showed relatively low YAP phosphorylation in the quantified immunoblot results. Indeed, TS with reduced YAP phosphorylation was associated with aggressive cancer phenotypes. Predominant nuclear localization of YAP and binding of YAP/TAZ to TEAD in the nucleus was evident in the TS15-88 cells. The YAP knockdown (KD) by siRNA significantly resulted decrease in TS proliferation through WST and ATP assay and values were validated again through YAP inhibitor, Verteporfin (VP). YAP KD attenuated not only the invasion and stemness of TS but also caused a reduction in tumor volume and prolonged the overall survival of mice.

CONCLUSION
We showed alteration of gene activities by YAP and nuclear localization of YAP/TAZ complex contributes to GBM progression. Moreover, thus tuning of Yap activity results a marked suppression in aggressive phenotypes of cancer. These associations emphasize that the YAP signaling network highly suggests new therapeutic opportunities in diagnosing and treating GBM.
CSIG-29. EMPLOYING THE ZIKA VIRUS AS ONCOLYTIC VIROTHERAPY AGAINST PAEDIATRIC NERVOUS SYSTEM CANCER CELLS
Authors: Sherwood Matthew , Kaid Carolini , Mitsugi Thiago , Zhou Yilu , Wang Yihua , Skipp Paul , Gray Juliet , Okamoto Oswaldo , Ewing Rob 
Published: November 2022

Abstract

BACKGROUND
Malignant paediatric nervous system tumours, such as medulloblastoma, ATRT and high-risk neuroblastoma commonly harbour tumour cells with stem-like features which are highly tumorigenic and resistant to conventional therapies. These tumours can exhibit high lethality and may result in severe sequelae that significantly affect paediatric patients' quality of life. Oncolytic virotherapy exploits viruses that preferentially infect and destroy tumour cells. These viruses present a unique advantage in targeting highly heterogeneous cancers as they possess a secondary mechanism of action, through which they induce an anti-tumoral immune response. The Zika virus (ZIKV) is capable of infecting and destroying aggressive human paediatric brain tumour and neuroblastoma cells in vitro. ZIKV effectively reduces brain tumour size in mice (xenograft model) and canines (naturally occurring) and can induce an immune response against canine brain tumours.

METHODS
Employing global expression omics profiling of ZIKV infection and mapping of viral protein-host protein interactions, we aim to elucidate the mechanisms which underpin ZIKVs therapeutic properties, both at the molecular and cellular pathway levels.

RESULTS
Through extensive transcriptome profiling of ZIKV-infected paediatric brain tumour, neuroblastoma and NPCs, we have identified a variety of pathways which are involved in the ZIKV oncolytic response in the tumour cells and its neuro-dysregulation of NPCs. Despite both brain tumour and neuroblastoma cells undergoing ZIKV-induced oncolysis, we observed there to be a heterogeneous response within these different tumour cells at the molecular level to lead to oncolysis. Additionally, the infected tumour cells demonstrate elevated immune system profiles which alludes to the immune response that ZIKV may raise within the patient’s body against the paediatric tumour. Analysing our findings alongside the neuro-dysregulation we observe in our ZIKV-infected NPCs is allowing us to build a safety profile for employing a ZIKV-based therapy, whilst contributing to the growing knowledge of Congenital ZIKV Syndrome.
CSIG-37. MERLIN S13 DEPHOSPHORYLATION DRIVES MENINGIOMA WNT SIGNALLING AND CELL PROLIFERATION
Authors: Eaton Charlotte , John Liu S , Lucas Calixto-Hope , Casey-Clyde Tim , Choudhury Abrar , Daggubati Vikas , Vasudevan Harish , Swaney Danielle , Raleigh David 
Published: November 2022

Abstract
How Merlin-intact meningiomas arise in the absence of NF2/Merlin inactivation is incompletely understood. Here, we integrate single-cell RNA sequencing of 86,000 cells from meningioma xenografts with APEX2 proteomic proximity-labelling mass spectrometry and functional biochemical approaches to discover Merlin Serine 13 (S13) dephosphorylation drives meningioma Wnt signalling and cell proliferation. Cell biology, molecular biology, and biochemical techniques were used to validate Merlin functions in meningioma cells or xenografts using wildtype Merlin constructs or Merlin constructs encoding S13A, phosphomimetic S13D, or cancer-associated missense substitutions (L46R, A211D). Single-cell RNA sequencing of meningioma xenografts showed Merlin rescue activated the Wnt pathway in Merlin-deficient meningiomas. Proteomic proximity-labelling mass spectrometry revealed b-catenin, PKC, and PP1A interactions with wildtype Merlin, but not with Merlin L46R or A211D. b-catenin does not interact with other FERM family members, and Merlin contains a unique N-terminal domain (NTD) with a PKC phosphorylation motif overlapping with a PP1A dephosphorylation motif at S13. Thus, we hypothesized the Merlin S13, PKC, and PP1A may be important for Wnt signalling in Merlin-intact meningiomas. In support of this hypothesis, over-expression of wildtype Merlin or Merlin S13A but not Merlin DNTD, S13D, L46R, A211D, or other FERM family members drove meningioma Wnt signalling and sustained meningioma cell proliferation in vivo. Moreover, b-catenin was detected in proximity to Merlin S13D but not Merlin S13A in meningioma cells. Meningioma cell fractionation and immunofluorescence showed Merlin S13D over-expression stabilized b-catenin at the plasma membrane and inhibited Wnt signalling. Phospho-proteomic mass spectrometry and custom phospho-specific antibodies integrated with shRNA or siRNA gene suppression demonstrated PKC phosphorylated Merlin S13, but meningioma Wnt pathway activation induced PP1A to dephosphorylate Merlin S13 and drive cell proliferation. In summary, Merlin S13 dephosphorylation drives meningioma Wnt signalling and cell proliferation. These data reveal a novel tumor-promoting function of NF2/Merlin in Merlin-intact meningiomas.
CSIG-38. ENGINEERED PULLULAN-COLLAGEN-GOLD NANO COMPOSITE IMPROVES MESENCHYMAL STEM CELLS NEURAL DIFFERENTIATION AND INFLAMMATORY REGULATION
Authors: Chen Tracy , Yang Meng-Yin 
Published: November 2022

Abstract
Tissue repair engineering supported by nanoparticles and stem cells is an efficient strategy for promoting the healing potential of damaged tissues. Tissue repair engineering supported by nanoparticles and stem cells is an efficient strategy for promoting the healing potential of damaged tissues. In this study, we prepared various nanomaterials including pure Pul, pure Col, Pul–Col, Pul–Au, Pul–Col–Au, and Col–Au to investigate their physicochemical properties, biocompatibility, biological functions, differentiation capacities, and anti-inflammatory abilities through in vitro and in vivo assessments. The physicochemical properties were characterized by SEM, DLS assay, contact angle measurements, UV-Vis spectra, FTIR spectra, SERS, and XPS analysis. Pul–Col–Au composite enhanced cell viability, promoted anti-oxidative ability for MSCs and HSFs, inhibited monocyte and platelet activation, induced the lowest cell apoptosis, facilitated the MMP activities and improved endothelialization. In conclusion, Pul–Col–Au nanoparticles are promising material for tissue regeneration.
CSIG-40. STEAROYL-COA DESATURASE 1 (SCD1) IS REQUIRED FOR WNT SIGNALING TO INDUCE AN APOPTOSIS IN IDH MUTANT GLIOMA
Authors: Zhang Lumin , Yamasaki Tomohiro , Dowdy Tyrone , Lita Adrian , Gilbert Mark , Larion Mioara 
Published: November 2022

Abstract

BACKGROUND AND HYPOTHESES
SCD1, a major enzyme of saturated fatty acids, has been implicated to be important for tumor metabolic reprograming. Our previous study show that a high level of SCD1 mRNA is associated with IDH1mut lower grade gliomas. IDH1mut glioma cells are more sensitive to SFA induced apoptosis. However, the underlying mechanism remains unclear. In this study, we investigate the functions of SCD1 in IDHmut glioma and the potential contribution of SCD1 for cancer therapy of glioma.

STUDY DESIGN AND METHODS
The genetically engineered IDH wild-type, IDHmut and patient derived glioma cell lines were used to evaluate SCD1 functions. The expression of proteins were checked by Western-blotting assay. SCD1 was silenced by CRISPR or siRNA. The transcriptome change after SCD1 knockdown was profiled by RNA-seq or single cell RNA-seq (scRNA-seq).

RESULTS AND CONCLUSIONS
SCD1 transient silencing slowed down the cell growth, suggesting that SCD1 may possess an oncogenic property. RNA-seq analysis revealed that SCD1 inhibition decreased the expression of wnt-signaling pathway genes in IDH-1mut cells. scRNA confirmed that CRISPR SCD1 significantly decreased wnt signaling in the patient cell line Ts603. Therefore, we activated wnt pathway using a small chemical compound, BML-2838. Consistent with recent studies, wnt pathway induction led to a dramatically suppression of glioma cells growth. However, SCD1 silencing reversed this inhibitory effect. Further investigation revealed that SCD1 inhibition reduced the nucleus translocation of phosphorylated beta-catenin. Overall, the results suggest that SCD1 is vital for the onset of wnt pathway in glioma cells. High level of SCD1 expression may render the IDHmut glioma cells more sensitive to wnt pathway induced apoptosis.

RELEVANCE AND IMPORTANCE
In clinical, the 5-years survival rate of glioma remains low. SCD1 have been considered as a target for glioma therapy, recently. Our data provides a new insight on the strategy to target SCD1 in clinical.
RADT-08. DOSIMETRIC FEASIBILITY OF DIRECT POST-OPERATIVE MRI-LINAC-BASED STEREOTACTIC RADIOSURGERY FOR RESECTION CAVITIES OF BRAIN METASTASES
Authors: Sierts M , Seravalli E , Brand E , Maspero M , David S , Philippens M E P , Voormolen E H J , Verhoeff J J C 
Published: November 2022

Abstract

Background
Post-operative stereotactic radiosurgery (SRS) of patients with brain metastases with single resection cavities is typically planned on a post-recovery MRI, 4-6 weeks after resection. However, meanwhile the intracranial metastasis may (re-)grow, and postponing adjuvant systemic treatment increases chance on extracranial progression as well. Anticipating direct post-operative SRS to minimize this interval would enable rapid start of systemic therapy. In this study, we considered treatment with MRI-Linac (MRL) SRS, because of the possibility to execute the post-operative MRI and SRS treatment combined on the MRL instead of on two separate systems, improving logistics and increasing patient comfort. However, it is unclear whether MRL-based SRS may be feasible from a dosimetric perspective. This study aims to shed light on the dosimetric feasibility of MRL-based SRS.

METHODS
We simulated MRL treatments including thirteen patients with resectable single brain metastases treated with single fraction CT-Linac (CTL) SRS. We therefore contoured direct post-operative gross tumor volumes (GTV) and compared them to post-recovery MRI GTV. Next, we compared a non-coplanar VMAT technique for CTL (ncVMAT) to a coplanar IMRT technique for MRL (cIMRT), creating three plans per patient: a ncVMAT plan and a cIMRT plan for the direct post-operative GTV, and a post-recovery ncVMAT plan as current clinical standard. RESULTSCompared to GTVs defined on direct post-operative MRI, on post-recovery MRI 15.5% of cavities shrunk by &gt; 2cc, and 46% expanded by &gt; 2cc. Although direct post-operative ncVMAT plans had lower median gradient index and higher median V3Gy of the skin, they were clinically acceptable according to clinical guidelines.

CONCLUSION
Although slightly inferior to non-coplanar CTL plans, direct post-operative MRL-based SRS for resection cavities of brain metastases is dosimetrically acceptable, at the trade-off between increased patient comfort and logistics. Additionally, MRL-based SRS enables substantially earlier start with adjuvant systemic therapies, thereby maximizing tumor control.
RADT-14. COMBINATION RE-RADIATION AND BEVACIZUMAB THERAPY FOR RECURRENT GLIOBLASTOMA: CLINICAL OUTCOMES OF 337 PATIENTS
Authors: Mekonnen Mahlet , Mozaffari Khashayar , Sparks Othneil , Umesh Amith , Zhang Ashley Bo , Yang Isaac 
Published: November 2022

Abstract

BACKGROUND
High-grade gliomas (HGGs) comprise the most common primary adult brain cancers and universally recur. Glioblastoma (GBM) compromise 60% of HGGs with an extremely poor prognosis and are considered incurable despite many treatment advancements. Combination re-radiation therapy (re-RT) and bevacizumab (BVZ) therapy for recurrent HGG is commonly used, however, there is a paucity of literature with respect to its efficacy.

OBJECTIVE
This study aimed to compare treatment outcomes of patients who received reRT alone versus a combination of reRT and BVZ (reRT ± BVZ ) to establish clear guidelines for the optimal management of recurrent GBM.

METHODS
We identified patients with recurrent GBM treated via reRT ± BVZ. Cohorts were stratified by BVZ treatment status and re-irradiation modality. Primary outcomes of interest included radiation necrosis (RN), progression-free survival (PFS), and overall survival (OS). These parameters were then compared between the reRT + BVZ and the reRT alone cohorts.

RESULTS
A total of 337 patients were included. Mean age at primary resection was 51 years old (range: 5-82). Of those, 223 (66.2%) were male and 114 (33.8%) were female. All patients were initially treated with surgical resection. Mean follow up for the entire cohort was 19.1 months (± 1.14 months). The re-RT + BVZ cohort had a longer median survival at 14 months with 6-, 12-, and 24- month survivals of 84%, 60%, and 19.4%, respectively compared to their re-RT alone counterparts. Our study suggests that the combination of reRT+BVZ is effective in improving overall survival and lowering radiation necrosis rates, compared to reRT alone.

CONCLUSIONS
Combination reRT+BVZ may improve OS and reduce rates of RN in recurrent GBM, but further controlled studies are warranted to validate these effects. Future studies should investigate optimal protocols for reRT+BVZ treatment, and for evaluating subsequent radiologic progression in patients with recurrent GBM.