Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1282739 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:NRCAM variant defined by microexon skipping is a targetable surface proteoform in high-grade gliomas
| PRJNA1285931 | ENA
Project description:Neuronal activity promotes high-grade glioma (HGG) growth. An important mechanism mediating this neural regulation of brain cancer is activity-dependent cleavage and secretion of the synaptic molecule and glioma mitogen neuroligin-3 (Nlgn3), but the therapeutic potential of targeting Nlgn3 in glioma remains to be defined. We demonstrate a striking dependence of HGG growth on microenvironmental Nlgn3 and determine a targetable mechanism of secretion. Patient-derived orthotopic xenografts of pediatric glioblastoma, diffuse intrinsic pontine glioma and adult glioblastoma fail to grow in Nlgn3 knockout mice. Glioma exposure to Nlgn3 results in numerous signaling consequences, including early focal adhesion kinase activation upstream of PI3K-mTOR. Nlgn3 is cleaved from both neurons and oligodendrocyte precursor cells via the ADAM10 sheddase. Administration of ADAM10 inhibitors robustly blocks HGG xenograft growth. This work defines the therapeutic potential of and a promising strategy for targeting Nlgn3 secretion in the glioma microenvironment, which could prove transformative for treatment of HGG.
2017-08-11 | GSE99045 | GEO
Project description:To overcome the paucity of known tumor-specific surface antigens in pediatric high-grade glioma (pHGG), we contrasted splicing patterns in pHGGs and normal brain samples. Among alternative splicing events affecting extracellular protein domains, the most pervasive alteration was the skipping of ≤30 nucleotide-long microexons. Several of these skipped microexons mapped to L1-IgCAM family members, such as NRCAM. Bulk and single-nuclei short- and long-read RNA-seq revealed uniform skipping of NRCAM microexons 5 and 19 in virtually every pHGG sample. Importantly, the Δex5Δex19 (but not the full-length) NRCAM proteoform was essential for pHGG cell migration and invasion in vitro and tumor growth in vivo. We developed a monoclonal antibody selective for Δex5Δex19 NRCAM and demonstrated that “painting“ of pHGG cells with this antibody enables killing by T cells armed with an FcRI-based universal immune receptor. Thus, pHGG-specific NRCAM and possibly other L1-IgCAM proteoforms are promising and highly selective targets for adoptive immunotherapies.
2025-08-05 | GSE301658 | GEO
Project description:Microexons (exons ≤30 nts) are important features of neuronal transcriptomes, but pose mechanistic challenges to the splicing machinery. We previously showed that PRP-40, a component of the U1 spliceosome, is globally required for microexon splicing in C. elegans. Here we show that the homologous PRPF40A is also globally required for microexon splicing in mouse neuroblastoma cells. We find that PRPF40A co-regulates microexons along with SRRM4, a neuron-specific regulator of microexon splicing. The relationship between exon size and dependence on PRPF40A/SRRM4 is distinct, with SRRM4-dependence exhibiting a size threshold (~30 nts) and PRPF40A-dependence exhibiting a graded decrease as exon size increases. Finally, we show that PRPF40A knockdown causes an increase in productive splicing of its spliceosomal binding partner Luc7l by skipping of a small “poison exon.” Similar homeostatic cross-regulation is often observed across paralogous RNA binding proteins. Here we find this concept likewise applies across evolutionarily unrelated but functionally and physically coupled spliceosomal components.
2024-11-05 | GSE267257 | GEO
Project description:Genome wide DNA methylation profiling of 112 human glioma samples. The Illumina Infinium 27k Human DNA methylation Beadchip v1.2 was used to obtain DNA methylation profiles across approximately 27,000 CpGs in glioma samples, including 55 WHO grade 2 glioma samples, 33 WHO grade 3 glioma samples and 24 WHO grade 4 glioma samples.
2013-12-12 | GSE53227 | GEO
Project description:Glioblastoma (GBM) is a lethal brain tumor without effective treatment options. Data about proteomics in glioma is sparse and it has not yet been integrated into the routine diagnostic work-up or exploited to find potential actionable targets to prevent GBM-induced immune evasion mechanisms and recurrence. We performed proteomic analysis of diffuse glioma samples classified into six subgroups defined by DNA methylation and patient-paired primary and recurrent samples in order to i) provide an inventory of proteins commonly or individually overexpressed in each of the four HGG subgroups compared to the LGG and deduce relevant pathways for each subgroup and ii) identify specific proteins involved in tumor recurrence after surgical removal.
The first study revealed largest differences between low-grade (LGG) and high-grade gliomas (HGG), with major changes observed in proteins involved in active calcium-dependent vesicle trafficking (S100 proteins and annexins), effectors of the immunological synapse, proteins involved in Retinoid acid signalling, and proteins involved in extracellular matrix, cytoskeleton, and cell adhesion. Comparative proteomic analysis between LGG and the HGG subgroups also showed consistency with glioma grading.
The second study identified FcGamma receptors on activated microglia and complement components as major players inducing short relapsing GBM tumors.
In conclusion, specific pathways and proteins represent potential targets to control progression of the distinct subgroups.
2023-04-19 | MSV000091739 | MassIVE
Project description:Genome wide DNA methylation profiling of 112 human glioma samples. The Illumina Infinium 27k Human DNA methylation Beadchip v1.2 was used to obtain DNA methylation profiles across approximately 27,000 CpGs in glioma samples, including 55 WHO grade 2 glioma samples, 33 WHO grade 3 glioma samples and 24 WHO grade 4 glioma samples. Bisulphite converted DNA from the 112 glioma samples were hybridised to the Illumina Infinium 27k Human Methylation Beadchip v1.2
2013-12-12 | E-GEOD-53227 | biostudies-arrayexpress
Project description:The concept that solid tumors are maintained by a productive interplay between neoplastic and non-neoplastic elements has gained traction with the demonstration that stromal fibroblasts and immune system cells dictate cancer development and progression. While less studied, brain tumor (glioma) biology is likewise influenced by non-neoplastic immune system cells (macrophages and microglia) which interact with neoplastic glioma cells to create a unique physiological state (glioma ecosystem) distinct from that found in the normal tissue. To explore this neoplastic ground state, we leveraged several preclinical mouse models of neurofibromatosis type 1 (NF1) optic glioma, a low-grade astrocytoma whose formation and maintenance requires productive interactions between non-neoplastic and neoplastic cells, and employed whole tumor RNA-sequencing and mathematical deconvolution strategies to characterize this low-grade glioma ecosystem as an aggregate of cellular and acellular elements. Using this approach, we demonstrate that optic gliomas generated by altering the germline Nf1 gene mutation, the glioma cell of origin, or the presence of co-existing genetic alterations represent molecularly-distinct tumors. However, these optic glioma tumors share a 25-gene core signature, not found in normal optic nerve, that is normalized by microglia inhibition (minocycline), but not conventional (carboplatin) or molecularly-targeted (rapamycin) chemotherapy. Lastly, we identify a genetic signature conferred by Pten reduction and corrected by PI3K inhibition. This signature predicts progression-free survival in patients with either low-grade or high-grade glioma. Collectively, these findings support the concept that gliomas are composite ecological systems whose biology and response to therapy may be best defined by examining the tumor as a whole.
2017-08-07 | GSE102345 | GEO