-
International Journal of Molecular... Apr 2024Medulloblastoma (MB) encompasses diverse subgroups, and leptomeningeal disease/metastasis (LMD) plays a substantial role in associated fatalities. Despite extensive...
Medulloblastoma (MB) encompasses diverse subgroups, and leptomeningeal disease/metastasis (LMD) plays a substantial role in associated fatalities. Despite extensive exploration of canonical genes in MB, the molecular mechanisms underlying LMD and the involvement of the orthodenticle homeobox 2 (OTX2) gene, a key driver in aggressive MB Group 3, remain insufficiently understood. Recognizing OTX2's pivotal role, we investigated its potential as a catalyst for aggressive cellular behaviors, including migration, invasion, and metastasis. OTX2 overexpression heightened cell growth, motility, and polarization in Group 3 MB cells. Orthotopic implantation of OTX2-overexpressing cells in mice led to reduced median survival, accompanied by the development of spinal cord and brain metastases. Mechanistically, OTX2 acted as a transcriptional activator of the Mechanistic Target of Rapamycin (mTOR) gene's promoter and the mTORC2 signaling pathway, correlating with upregulated downstream genes that orchestrate cell motility and migration. Knockdown of mTOR mRNA mitigated OTX2-mediated enhancements in cell motility and polarization. Analysis of human MB tumor samples (N = 952) revealed a positive correlation between OTX2 and mTOR mRNA expression, emphasizing the clinical significance of OTX2's role in the mTORC2 pathway. Our results reveal that OTX2 governs the mTORC2 signaling pathway, instigating LMD in Group 3 MBs and offering insights into potential therapeutic avenues through mTORC2 inhibition.
Topics: Animals; Female; Humans; Male; Mice; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cerebellar Neoplasms; Gene Expression Regulation, Neoplastic; Mechanistic Target of Rapamycin Complex 2; Medulloblastoma; Meningeal Neoplasms; Otx Transcription Factors; Signal Transduction
PubMed: 38674001
DOI: 10.3390/ijms25084416 -
Cancers Apr 2024Medulloblastoma and pilocytic astrocytoma are the two most common pediatric brain tumors with overlapping imaging features. In this proof-of-concept study, we...
Medulloblastoma and pilocytic astrocytoma are the two most common pediatric brain tumors with overlapping imaging features. In this proof-of-concept study, we investigated using a deep learning classifier trained on a multicenter data set to differentiate these tumor types. We developed a patch-based 3D-DenseNet classifier, utilizing automated tumor segmentation. Given the heterogeneity of imaging data (and available sequences), we used all individually available preoperative imaging sequences to make the model robust to varying input. We compared the classifier to diagnostic assessments by five readers with varying experience in pediatric brain tumors. Overall, we included 195 preoperative MRIs from children with medulloblastoma ( = 69) or pilocytic astrocytoma ( = 126) across six university hospitals. In the 64-patient test set, the DenseNet classifier achieved a high AUC of 0.986, correctly predicting 62/64 (97%) diagnoses. It misclassified one case of each tumor type. Human reader accuracy ranged from 100% (expert neuroradiologist) to 80% (resident). The classifier performed significantly better than relatively inexperienced readers ( < 0.05) and was on par with pediatric neuro-oncology experts. Our proof-of-concept study demonstrates a deep learning model based on automated tumor segmentation that can reliably preoperatively differentiate between medulloblastoma and pilocytic astrocytoma, even in heterogeneous data.
PubMed: 38672556
DOI: 10.3390/cancers16081474 -
Cells Apr 2024Transglutaminase type 2 (TG2) is the most ubiquitously expressed member of the transglutaminase family. TG2 catalyzes the transamidation reaction leading to several... (Review)
Review
Transglutaminase type 2 (TG2) is the most ubiquitously expressed member of the transglutaminase family. TG2 catalyzes the transamidation reaction leading to several protein post-translational modifications and it is also implicated in signal transduction thanks to its GTP binding/hydrolyzing activity. In the nervous system, TG2 regulates multiple physiological processes, such as development, neuronal cell death and differentiation, and synaptic plasticity. Given its different enzymatic activities, aberrant expression or activity of TG2 can contribute to tumorigenesis, including in peripheral and central nervous system tumors. Indeed, TG2 dysregulation has been reported in meningiomas, medulloblastomas, neuroblastomas, glioblastomas, and other adult-type diffuse gliomas. The aim of this review is to provide an overview of the biological and functional relevance of TG2 in the pathogenesis of nervous system tumors, highlighting its involvement in survival, tumor inflammation, differentiation, and in the resistance to standard therapies.
Topics: Animals; Humans; GTP-Binding Proteins; Nervous System Neoplasms; Protein Glutamine gamma Glutamyltransferase 2; Transglutaminases
PubMed: 38667282
DOI: 10.3390/cells13080667 -
Nature Communications Apr 2024Chemical discovery efforts commonly target individual protein domains. Many proteins, including the EP300/CBP histone acetyltransferases (HATs), contain several...
Chemical discovery efforts commonly target individual protein domains. Many proteins, including the EP300/CBP histone acetyltransferases (HATs), contain several targetable domains. EP300/CBP are critical gene-regulatory targets in cancer, with existing high potency inhibitors of either the catalytic HAT domain or protein-binding bromodomain (BRD). A domain-specific inhibitory approach to multidomain-containing proteins may identify exceptional-responding tumor types, thereby expanding a therapeutic index. Here, we discover that targeting EP300/CBP using the domain-specific inhibitors, A485 (HAT) or CCS1477 (BRD) have different effects in select tumor types. Group 3 medulloblastoma (G3MB) cells are especially sensitive to BRD, compared with HAT inhibition. Structurally, these effects are mediated by the difluorophenyl group in the catalytic core of CCS1477. Mechanistically, bromodomain inhibition causes rapid disruption of genetic dependency networks that are required for G3MB growth. These studies provide a domain-specific structural foundation for drug discovery efforts targeting EP300/CBP and identify a selective role for the EP300/CBP bromodomain in maintaining genetic dependency networks in G3MB.
Topics: Humans; Medulloblastoma; E1A-Associated p300 Protein; Cell Line, Tumor; Gene Regulatory Networks; Animals; Protein Domains; Gene Expression Regulation, Neoplastic; Mice; Cerebellar Neoplasms; Antineoplastic Agents
PubMed: 38664416
DOI: 10.1038/s41467-024-47102-0 -
Turkish Neurosurgery 2024To evaluate the efficacy of percutaneous ventriculoatrial shunting as a salvage method for pediatric patients with abdominal complications.
AIM
To evaluate the efficacy of percutaneous ventriculoatrial shunting as a salvage method for pediatric patients with abdominal complications.
MATERIAL AND METHODS
Data obtained from 9 patients with ventriculoperitoneal shunt dysfunctions owing to abdominal complications, who underwent ventriculoatrial shunting as salvage treatment at a single institution between January 2019 and September 2021 were retrospectively analyzed. All operations were conducted under the guidance of intraoperative fluoroscopy and ultrasound.
RESULTS
The mean age of the enrolled patients was 8.1 ± 1.2 years (2-15 years). Six (67%) patients were male and 3 (33%) were female. The mean number of the patients? ventriculoperitoneal shunt revisions until atrial catheter placement was 7.5 times. The reasons for intraperitoneal catheter failure included peritoneal adhesions in 4 (44.5%) patients, pseudocyst formation in 3 (33.3%), and peritonitis in 2 (22.2%). Seven patients from the study cohort had no problem after ventriculoatrial shunt placement. Only 1 patient had shunt dysfunction related to the ventricular catheter, and ventricular catheter and shunt valve revision was performed 26 months after ventriculoatrial shunt placement. The atrial catheter of the patient was intact. One patient died from the progression of her primary disease (medulloblastoma in the 4 < sup > th < /sup > ventricle), which was unrelated to the ventriculoatrial shunt.
CONCLUSION
Percutaneous ventriculoatrial shunting under the guidance of intraoperative fluoroscopy and ultrasound is a safe, effective, and easy alternative in patients with peritoneal complications and a history of multiple operations.
Topics: Humans; Female; Hydrocephalus; Child; Male; Child, Preschool; Adolescent; Ventriculoperitoneal Shunt; Retrospective Studies; Salvage Therapy; Treatment Outcome; Postoperative Complications; Reoperation
PubMed: 38650557
DOI: 10.5137/1019-5149.JTN.43472-23.2 -
World Neurosurgery Apr 2024Medulloblastomas are the most common malignant brain tumors in the pediatric population. Based on the idea that tumors with identical radio-genomic features should...
BACKGROUND
Medulloblastomas are the most common malignant brain tumors in the pediatric population. Based on the idea that tumors with identical radio-genomic features should behave similarly, the 4 molecular subtypes are now widely accepted as a guide for the management and prognosis. The radiological features of medulloblastomas can predict the molecular subtype; thus, anticipating the subsequent disease progression. However, this has not been evaluated comprehensively. We aim to thoroughly study the association between the molecular subtypes and radiological features of medulloblastomas. Moreover, we aim to investigate the efficacy of this correlation with the use of progression-free survival and 5-year survival rates.
METHODS
A retrospective analysis was conducted for all histopathological confirmed medulloblastomas in pediatric patients (<16 years old) that were operated on in Kuwait over the past ten years (n = 44). The radiological, histological, and molecular characteristics were justifiably evaluated and analyzed in our sample.
RESULTS
The overall progression-free survival after one year was noticed among 27 cases (≈44%) and the nonspecific 5-year survival was seen in 31 cases (≈70%) after a 5-year follow-up. Sonic Hedgehog and Wingless had the best outcomes, while group 3 showed the worst outcomes.
CONCLUSIONS
Our findings did not support the association between most of the typical magnetic resonance imaging characteristics and survival rate. We further established that Sonic Hedgehog and Wingless biological types have a better prognosis. There was no association observed between the radiographic features, specifically the location, and the molecular subtype.
PubMed: 38636638
DOI: 10.1016/j.wneu.2024.04.057 -
Cancer Gene Therapy Jun 2024Medulloblastoma (MB), a prevalent pediatric central nervous system tumor, is influenced by microRNAs (miRNAs) that impact tumor initiation and progression. However, the...
Medulloblastoma (MB), a prevalent pediatric central nervous system tumor, is influenced by microRNAs (miRNAs) that impact tumor initiation and progression. However, the specific involvement of miRNAs in MB tumorigenesis remains unclear. Using single-cell RNA sequencing, we identified ROR2 expression in normal human fetal cerebellum. Subsequent analyses, including immunofluorescence, quantitative real-time PCR (qRT-PCR), and Western blot, assessed ROR2 expression in MB tissues and cell lines. We investigated miR-124-3p and miR-194-5p and their regulatory role in ROR2 expression through the dual-luciferase reporter, qRT-PCR, and western blot assays. Mechanistic insights were gained through functional assays exploring the impact of miR-124-3p, miR-194-5p, and ROR2 on MB growth in vitro and in vivo. We observed significantly reduced miR-124-3p and miR-194-5p expression and elevated ROR2 expression in MB tissues and cell lines. High ROR2 expression inversely correlated with overall survival in WNT and SHH subgroups of MB patients. Functionally, overexpressing miR-124-3p and miR-194-5p and inhibiting ROR2 suppressed in vitro malignant transformation and in vivo tumorigenicity. Mechanistically, miR-124-3p and miR-194-5p synergistically regulated the ROR2/PI3K/Akt pathway, influencing MB progression. Our findings indicate that miR-124-3p and miR-194-5p function as tumor suppressors, inhibiting MB progression via the ROR2/PI3K/Akt axis, suggesting a key mechanism and therapeutic targets for MB patients.
Topics: Humans; MicroRNAs; Medulloblastoma; Receptor Tyrosine Kinase-like Orphan Receptors; Proto-Oncogene Proteins c-akt; Mice; Animals; Phosphatidylinositol 3-Kinases; Disease Progression; Cerebellar Neoplasms; Signal Transduction; Gene Expression Regulation, Neoplastic; Female; Male; Cell Line, Tumor; Cell Proliferation
PubMed: 38632356
DOI: 10.1038/s41417-024-00762-y -
Clinical and Translational Radiation... May 2024As craniospinal irradiation (CSI) is delivered more frequently by helical tomotherapy (HT) with few reports about late effects, we analysed all patients treated in our...
OBJECTIVE
As craniospinal irradiation (CSI) is delivered more frequently by helical tomotherapy (HT) with few reports about late effects, we analysed all patients treated in our centre over an 11-year period.
METHODS AND MATERIALS
Our study included all patients that underwent CSI by HT, between September 2009 and January 2020, in the Department of Radiation Oncology of the Toulouse Cancer Institute. Acute radiotherapy toxicities were reported and medium- to long-term outcomes analysed.
RESULTS
Among the 79 patients included, 70.9 % were younger than 18 years at diagnosis, the median age was 13 (range: 1-52) at the time of radiation therapy, 67.1 % of patients had medulloblastoma. Half of them (49.4 %) had a metastatic disease at diagnosis. The median dose of CSI was 36 Gy (range, 18-36). Seventy-seven patients received a radiation boost to the original location of the primary tumour (97.5 %), 32 patients also received a boost to their metastatic sites (40.5 %). Median follow-up was 55.5 months (95 %CI = [41.2; 71.8]). The 3-year event-free survival rate was 66.3 % (95 %CI = [54.2; 75.9]). Most patients presented with acute haematological toxicities during CSI (85.9 %), predominantly severe thrombocytopenia (39.7 %). Among the 64 patients assessed for medium- and long-term outcomes, 52 survived and 47 were alive and disease-free at the latest follow-up visit on record. There were 3.8 % secondary tumours: two meningiomas and one diffuse intrinsic pontine glioma. Adult and paediatric patients respectively presented with secondary cataract (4.3 % vs 22.0 %), persistent hearing disorders (26.1 % vs 29.3 %), pulmonary or cardiac late effects (4.3 % vs 2.4 %), hormonal pituitary gland deficiencies (30.0 % vs 56.8 %) and psycho-cognitive disorders (56.5 % vs 53.7 %).
CONCLUSION
CSI dispensed by HT, did not result in any additional acute or late toxicities when compared to 3D-CSI. There was no increase in the secondary tumour rate compared to that reported in the literature.
PubMed: 38628594
DOI: 10.1016/j.ctro.2024.100777 -
Pflugers Archiv : European Journal of... Jun 2024Fast growing solid tumors are frequently surrounded by an acidic microenvironment. Tumor cells employ a variety of mechanisms to survive and proliferate under these...
Functional expression of the proton sensors ASIC1a, TMEM206, and OGR1 together with BK channels is associated with cell volume changes and cell death under strongly acidic conditions in DAOY medulloblastoma cells.
Fast growing solid tumors are frequently surrounded by an acidic microenvironment. Tumor cells employ a variety of mechanisms to survive and proliferate under these harsh conditions. In that regard, acid-sensitive membrane receptors constitute a particularly interesting target, since they can affect cellular functions through ion flow and second messenger cascades. Our knowledge of these processes remains sparse, however, especially regarding medulloblastoma, the most common pediatric CNS malignancy. In this study, using RT-qPCR, whole-cell patch clamp, and Ca-imaging, we uncovered several ion channels and a G protein-coupled receptor, which were regulated directly or indirectly by low extracellular pH in DAOY and UW228 medulloblastoma cells. Acidification directly activated acid-sensing ion channel 1a (ASIC1a), the proton-activated Cl channel (PAC, ASOR, or TMEM206), and the proton-activated G protein-coupled receptor OGR1. The resulting Ca signal secondarily activated the large conductance calcium-activated potassium channel (BK). Our analyses uncover a complex relationship of these transmembrane proteins in DAOY cells that resulted in cell volume changes and induced cell death under strongly acidic conditions. Collectively, our results suggest that these ion channels in concert with OGR1 may shape the growth and evolution of medulloblastoma cells in their acidic microenvironment.
Topics: Humans; Acid Sensing Ion Channels; Medulloblastoma; Cell Line, Tumor; Receptors, G-Protein-Coupled; Hydrogen-Ion Concentration; Cell Size; Cell Death; Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; Calcium; Cerebellar Neoplasms
PubMed: 38627262
DOI: 10.1007/s00424-024-02964-7 -
International Journal of Molecular... Mar 2024Medulloblastoma (MB) is a highly malignant childhood brain tumor. Group 3 MB (Gr3 MB) is considered to have the most metastatic potential, and tailored therapies for Gr3...
Medulloblastoma (MB) is a highly malignant childhood brain tumor. Group 3 MB (Gr3 MB) is considered to have the most metastatic potential, and tailored therapies for Gr3 MB are currently lacking. Gr3 MB is driven by PRUNE-1 amplification or overexpression. In this paper, we found that PRUNE-1 was transcriptionally regulated by lysine demethylase LSD1/KDM1A. This study aimed to investigate the therapeutic potential of inhibiting both PRUNE-1 and LSD1/KDM1A with the selective inhibitors AA7.1 and SP-2577, respectively. We found that the pharmacological inhibition had a substantial efficacy on targeting the metastatic axis driven by PRUNE-1 (PRUNE-1-OTX2-TGFβ-PTEN) in Gr3 MB. Using RNA seq transcriptomic feature data in Gr3 MB primary cells, we provide evidence that the combination of AA7.1 and SP-2577 positively affects neuronal commitment, confirmed by glial fibrillary acidic protein (GFAP)-positive differentiation and the inhibition of the cytotoxic components of the tumor microenvironment and the epithelial-mesenchymal transition (EMT) by the down-regulation of N-Cadherin protein expression. We also identified an impairing action on the mitochondrial metabolism and, consequently, oxidative phosphorylation, thus depriving tumors cells of an important source of energy. Furthermore, by overlapping the genomic mutational signatures through WES sequence analyses with RNA seq transcriptomic feature data, we propose in this paper that the combination of these two small molecules can be used in a second-line treatment in advanced therapeutics against Gr3 MB. Our study demonstrates that the usage of PRUNE-1 and LSD1/KDM1A inhibitors in combination represents a novel therapeutic approach for these highly aggressive metastatic MB tumors.
Topics: Humans; Child; Medulloblastoma; Brain Neoplasms; Cerebellar Neoplasms; Histone Demethylases; Epigenesis, Genetic; Tumor Microenvironment
PubMed: 38612726
DOI: 10.3390/ijms25073917