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PROVIDER: PRJNA1201858 | ENA |
REPOSITORIES: ENA
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Project description:Background Heterogeneous clinical features and prognosis in neuroblastoma (NB) children are frequently dominated by immune elements. Dysfunction and apoptosis in immune cells result from the exposure to continuous tumor-related antigen stimulation and coinhibitory signals. To date, key factors pointing to the restriction of NB-specific CD8+T cells remain elusive. Methods We performed bulk-RNA sequencing and lipidomic analyses of children with mediastinal neuroblastoma. Bioinformatics analysis and validation of molecular biology assays were applied to uncover the underlying mechanism. Results Three subtypes were identified using nonnegative matrix factorization (NMF), we highlighted an apoptotic status of infiltrated CD8+T cells, along with the highest CD52 expression in Cluster3 (C3) subtypes, and verified high EDF1 expression in NB cells led to Lactosylceramide (LacCer) and downstream ganglioside-GD3 accumulation, which subsequently increased chemotaxis, CD52 and immune checkpoint expression, and apoptosis-related events in activated CD8+T cells. Mechanistically, EDF1 was recruited as a coactivator to form the NF-κB/RelA/EDF1 complex, which prevented the methylation of targeted site after binding to the promoter of GD3 synthase ST8SIA1, resulting in elevated ST8SIA1 transcription. Conclusion These findings characterizes the content of GD3 in NB cells, which is regulated by the EDF1/RelA/ST8SIA1 axis, is responsible for CD8+T cell dysfunction and inducing immune escape of NB cells. Inhibiting EDF1 may decreases suppressive factors and resolve apoptotic CD8+T cells. Controlling NB-associated GD3 levels through metabolic intervention is beneficial for tuning the depth and duration of response to current NB therapies.The integration of transcriptomic and lipidomic data provided a better understanding of the interaction between LacCer metabolites and the immune status in NB.
2025-02-12 | GSE285546 | GEO
Project description:Aging is marked by a progressive decline in physiological function, leading to an increased susceptibility to age-related diseases and cancer. On the cellular level, aging correlates with an accumulation of senescent cells, which play a dual role: they are critical for tissue homeostasis, yet their over-accumulation may drive pathological aging. We recently revealed that senescent cells could overexpress immunosuppressive molecules like the ganglioside GD3 at their cell surface to evade from immune surveillance and to facilitate their tolerogenicity. We investigate which cells expressed GD3 and whether this ganglioside could be considered as a new marker associated to senescence in a model of senescence associated disease: Bleomycin-induced lung fibrosis.
2024-04-04 | GSE262926 | GEO
Project description:Dr. Ladisch's work focuses on the establishment of the biological significance of gangliosides that are shed by tumor cells, particularly those involved in pediatric cancers, including brain tumors and neuroblastoma. These studies are directed toward illuminating the hypothesis that shed gangliosides enhance tumor formation, possibly both by inhibiting the antitumor immune response and by enhancing growth factor-induced signaling and proliferation of fibrobalsts and vascular endotheilial cells in the tumor microenvironment. Delineation of the signaling pathways affected by ganglioside exposure is currently under study. The effect of retinoic acid on the mRNA levels of ganglioside glycosyltransferases in neuroblastoma cells in vitro Experiment to determine mRNA expression for ganglioside glycosyltransferases in NB cells (untreated versus treated with ATRA) using the Glyco-gene Chip by the Consortium for Functional Glycomics. Human NB cell lines LAN-5 were incubated with 10 µM of all-trans retinoic acid or untreated as control, and total RNA harvested after 24 hours, 72 hours and 120 hours of exposure to retinoic acid. We performed three independent experiments on either cell line so that for each cell line and each time point three replicates were be obtained (total: 18 chips). Glycosyltransferases of particular interest are LacCer synthase, GlucCer synthase, GM3 synthase, GD3 synthase, GM2/GD2 synthase, GD1b/GM1a synthase, GT1b/GD1a synthase and GQ1b/GT1a synthase.
2011-01-07 | E-GEOD-26481 | biostudies-arrayexpress
Project description:GD2 is a disialoganglioside that is highly expressed on the surface of neuroblastoma cells. Immunotherapy with anti-GD2 antibodies has revolutionized the treatment of children with high-risk neuroblastoma, but nearly half of patients relapse and little is known about mechanisms of resistance to anti-GD2. Neuroblastomas harbor intrinsic transcriptional plasticity by co-opting divergent lineage-specific developmental programs between adrenergic and mesenchymal cell states. We found that reduced GD2 expression was significantly correlated with the adrenergic cell state in neuroblastoma and that an Adrenergic-to-Mesenchymal Transition (AMT) conferred downregulation of GD2 and resistance to anti-GD2 antibody. Induced reprogramming of adrenergic cells with the master AMT regulator PRRX1 was sufficient to promote transcriptional rewiring in isogenic models and downregulate GD2 expression. Mechanistically, low-GD2 expressing cell lines demonstrate significantly reduced expression of the ganglioside synthesis enzyme ST8SIA1 (GD3 synthase), resulting in a bottlenecking of GD2 synthesis. Primary neuroblastoma tumors enriched for mesenchymal features show demonstrably lower GD3 synthase expression as compared to adrenergic tumors. Pharmacologic inhibition of EZH2 resulted in epigenetic rewiring of mesenchymal neuroblastoma cells and re-expression of ST8SIA1, restoring surface expression of GD2 and sensitivity to an anti-GD2 antibody. These data identify developmental lineage as a key determinant of sensitivity to anti-GD2 based immunotherapies and credential EZH2 inhibitors for clinical testing in combination with anti-GD2 antibody to enhance outcomes for children with neuroblastoma.
2022-04-26 | GSE196861 | GEO
Project description:GD2 is a disialoganglioside that is highly expressed on the surface of neuroblastoma cells. Immunotherapy with anti-GD2 antibodies has revolutionized the treatment of children with high-risk neuroblastoma, but nearly half of patients relapse and little is known about mechanisms of resistance to anti-GD2. Neuroblastomas harbor intrinsic transcriptional plasticity by co-opting divergent lineage-specific developmental programs between adrenergic and mesenchymal cell states. We found that reduced GD2 expression was significantly correlated with the adrenergic cell state in neuroblastoma and that an Adrenergic-to-Mesenchymal Transition (AMT) conferred downregulation of GD2 and resistance to anti-GD2 antibody. Induced reprogramming of adrenergic cells with the master AMT regulator PRRX1 was sufficient to promote transcriptional rewiring in isogenic models and downregulate GD2 expression. Mechanistically, low-GD2 expressing cell lines demonstrate significantly reduced expression of the ganglioside synthesis enzyme ST8SIA1 (GD3 synthase), resulting in a bottlenecking of GD2 synthesis. Primary neuroblastoma tumors enriched for mesenchymal features show demonstrably lower GD3 synthase expression as compared to adrenergic tumors. Pharmacologic inhibition of EZH2 resulted in epigenetic rewiring of mesenchymal neuroblastoma cells and re-expression of ST8SIA1, restoring surface expression of GD2 and sensitivity to an anti-GD2 antibody. These data identify developmental lineage as a key determinant of sensitivity to anti-GD2 based immunotherapies and credential EZH2 inhibitors for clinical testing in combination with anti-GD2 antibody to enhance outcomes for children with neuroblastoma.
2022-04-26 | GSE180509 | GEO
Project description:GD2 is a disialoganglioside that is highly expressed on the surface of neuroblastoma cells. Immunotherapy with anti-GD2 antibodies has revolutionized the treatment of children with high-risk neuroblastoma, but nearly half of patients relapse and little is known about mechanisms of resistance to anti-GD2. Neuroblastomas harbor intrinsic transcriptional plasticity by co-opting divergent lineage-specific developmental programs between adrenergic and mesenchymal cell states. We found that reduced GD2 expression was significantly correlated with the adrenergic cell state in neuroblastoma and that an Adrenergic-to-Mesenchymal Transition (AMT) conferred downregulation of GD2 and resistance to anti-GD2 antibody. Induced reprogramming of adrenergic cells with the master AMT regulator PRRX1 was sufficient to promote transcriptional rewiring in isogenic models and downregulate GD2 expression. Mechanistically, low-GD2 expressing cell lines demonstrate significantly reduced expression of the ganglioside synthesis enzyme ST8SIA1 (GD3 synthase), resulting in a bottlenecking of GD2 synthesis. Primary neuroblastoma tumors enriched for mesenchymal features show demonstrably lower GD3 synthase expression as compared to adrenergic tumors. Pharmacologic inhibition of EZH2 resulted in epigenetic rewiring of mesenchymal neuroblastoma cells and re-expression of ST8SIA1, restoring surface expression of GD2 and sensitivity to an anti-GD2 antibody. These data identify developmental lineage as a key determinant of sensitivity to anti-GD2 based immunotherapies and credential EZH2 inhibitors for clinical testing in combination with anti-GD2 antibody to enhance outcomes for children with neuroblastoma.
2022-04-26 | GSE180514 | GEO
Project description:GD2 is a disialoganglioside that is highly expressed on the surface of neuroblastoma cells. Immunotherapy with anti-GD2 antibodies has revolutionized the treatment of children with high-risk neuroblastoma, but nearly half of patients relapse and little is known about mechanisms of resistance to anti-GD2. Neuroblastomas harbor intrinsic transcriptional plasticity by co-opting divergent lineage-specific developmental programs between adrenergic and mesenchymal cell states. We found that reduced GD2 expression was significantly correlated with the adrenergic cell state in neuroblastoma and that an Adrenergic-to-Mesenchymal Transition (AMT) conferred downregulation of GD2 and resistance to anti-GD2 antibody. Induced reprogramming of adrenergic cells with the master AMT regulator PRRX1 was sufficient to promote transcriptional rewiring in isogenic models and downregulate GD2 expression. Mechanistically, low-GD2 expressing cell lines demonstrate significantly reduced expression of the ganglioside synthesis enzyme ST8SIA1 (GD3 synthase), resulting in a bottlenecking of GD2 synthesis. Primary neuroblastoma tumors enriched for mesenchymal features show demonstrably lower GD3 synthase expression as compared to adrenergic tumors. Pharmacologic inhibition of EZH2 resulted in epigenetic rewiring of mesenchymal neuroblastoma cells and re-expression of ST8SIA1, restoring surface expression of GD2 and sensitivity to an anti-GD2 antibody. These data identify developmental lineage as a key determinant of sensitivity to anti-GD2 based immunotherapies and credential EZH2 inhibitors for clinical testing in combination with anti-GD2 antibody to enhance outcomes for children with neuroblastoma.
2022-04-26 | GSE180512 | GEO
Project description:GD2 is a disialoganglioside that is highly expressed on the surface of neuroblastoma cells. Immunotherapy with anti-GD2 antibodies has revolutionized the treatment of children with high-risk neuroblastoma, but nearly half of patients relapse and little is known about mechanisms of resistance to anti-GD2. Neuroblastomas harbor intrinsic transcriptional plasticity by co-opting divergent lineage-specific developmental programs between adrenergic and mesenchymal cell states. We found that reduced GD2 expression was significantly correlated with the adrenergic cell state in neuroblastoma and that an Adrenergic-to-Mesenchymal Transition (AMT) conferred downregulation of GD2 and resistance to anti-GD2 antibody. Induced reprogramming of adrenergic cells with the master AMT regulator PRRX1 was sufficient to promote transcriptional rewiring in isogenic models and downregulate GD2 expression. Mechanistically, low-GD2 expressing cell lines demonstrate significantly reduced expression of the ganglioside synthesis enzyme ST8SIA1 (GD3 synthase), resulting in a bottlenecking of GD2 synthesis. Primary neuroblastoma tumors enriched for mesenchymal features show demonstrably lower GD3 synthase expression as compared to adrenergic tumors. Pharmacologic inhibition of EZH2 resulted in epigenetic rewiring of mesenchymal neuroblastoma cells and re-expression of ST8SIA1, restoring surface expression of GD2 and sensitivity to an anti-GD2 antibody. These data identify developmental lineage as a key determinant of sensitivity to anti-GD2 based immunotherapies and credential EZH2 inhibitors for clinical testing in combination with anti-GD2 antibody to enhance outcomes for children with neuroblastoma.
2022-04-26 | GSE180515 | GEO
Project description:GM1 gangliosidosis is a neurodegenerative disorder caused by mutations in theGLB1gene, which encodes lysosomalb-galactosidase. The enzyme deficiency blocks GM1 ganglioside catabolism, leading to accumulation of GM1 ganglioside and asialo-GM1 ganglioside (GA1 glycolipid) in brain. This disease can present in varying degrees of severity, with the level of residualb-galactosidase activity primarily determining the clinical course.Glb1null mouse models, which completely lackb-galactosidase expression, exhibit a less severe form of the disease than expected from the comparable deficiency in humans, suggesting a potential species difference in the GM1 ganglioside degradation pathway. We hypothesized this difference may involve the sialidase NEU3, which acts on GM1 ganglioside to produce GA1 glycolipid. To test this hypothesis, we generatedGlb1/Neu3double knockout (DKO) mice. These mice had a significantly shorter lifespan, increased neurodegeneration, and more severe ataxia thanGlb1KO mice.Glb1/Neu3DKO mouse brains exhibited an increased GM1 ganglioside to GA1 glycolipid ratio compared withGlb1KO mice, indicating that Neu3 mediated GM1 ganglioside to GA1 glycolipid conversion inGlb1KO mice. The expression of genes associated with neuroinflammation and glial responses were enhanced inGlb1/Neu3DKO mice compared withGlb1KO mice. Mouse Neu3 more efficiently converted GM1 ganglioside to GA1 glycolipid than human NEU3 did. Our findings highlight Neu3’s role in ameliorating the consequences ofGlb1deletion in mice, provide insights into NEU3’s differential effects between mice and humans in GM1 gangliosidosis, and offer a potential therapeutic approach for reducing toxic GM1 ganglioside accumulation in GM1 gangliosidosis patients.
2023-12-14 | GSE241844 | GEO
Project description:Neuroblastoma (NB) is the most common extracranial pediatric solid tumor originating from the abnormal development of cells of the sympathoadrenal lineage of the neural crest. Targeting GD2 ganglioside (GD2), a glycolipid expressed on neuroblastoma cells, with GD2 ganglioside-recognizing antibodies affects several pivotal signaling routes that drive or influence the malignant phenotype of the cells. Previously performed gene expression profiling helped us to identify the PHLDA1 (pleckstrin homology-like domain family A member 1) gene as the most upregulated gene in the IMR-32 human neuroblastoma cells treated with the mouse 14G2a monoclonal antibody. Mass spectrometry-based proteomic analyses were applied to better characterize a role of PHLDA1 protein in the response of neuroblastoma cells to chimeric ch14.18/CHO antibody. Additionally, global protein expression profile analysis in the IMR-32 cell line with PHLDA1 silencing revealed increase in biological functions of mitochondria, accompanied by differentiation-like phenotype of the cells. Moreover, mass spectrometry analysis of the proteins co-immunoprecipitated using anti-PHLDA1-specific antibody, selected a group of possible PHLDA1 binding partners. Also, a more detailed analysis suggested that PHLDA1 interacts with the DCAF7/AUTS2 complex, a key component of neuronal differentiation in vitro.
2024-02-15 | PXD044319 | Pride