Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA159209 | ENA |
REPOSITORIES: ENA
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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:The tumor-associated glycosphingolipid ganglioside GD2 presents an attractive target for cancer immunotherapy. This molecule is abundant on different types of cancer cells and is characterized by restricted expression on healthy cells. Tumors exhibit heterogeneity in the expression level of GD2 and, therefore, development of methods for determination of the GD2-positive tumor phenotype for the pertinent application of targeted therapies is required. In this work, we have developed a gene expression-based classifier for the prediction of the GD2-positive tumor phenotype. We analyze RNA-seq data from GD2-positive and GD2-negative cell lines of different tumor types as well as neuroblastoma biopsy material for gene expression levels of enzymes that participate in ganglioside biosynthesis and determine the role of gene expression of these enzymes in the formation of the GD2-positive tumor phenotype. We also apply gene expression patterns known from literature to our data and use large public RNA-seq datasets to identify novel gene expression patterns associated with GD2 expression to validate the findings in our data. The results of the study may be used for the development of a gene signature which separates GD2-positive from GD2-negative tumors and for prediction of the GD2 phenotype in clinical specimens from cancer patients, and thus be used as a companion diagnostic for anti-GD2 therapy.
2019-12-19 | GSE142293 | 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 | 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 | GSE180515 | 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 | GSE180509 | 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
Project description:Extranodal natural killer (NK)/T-cell lymphoma, nasal type (ENKL), known for its poor prognosis and association with Epstein-Barr virus, has a new development with the establishment of the ENKL-J1 cell line. Derived from a patient's bone marrow, ENKL-J1 cells express the ganglioside GD2, making them targets for GD2-directed chimeric antigen receptor T cells. This discovery positions GD2 as a potential therapeutic target. Genetic analysis of ENKL-J1 revealed variants in TP53 and TET2. Single-cell RNA sequencing indicated high expression of genes in key oncogenic pathways such as JAK-STAT, NF-κB, and MAPK, along with genes linked to multidrug resistance, tumor suppression, and anti-apoptosis. In vitro, molecular targeting agents like eprenetapopt, tazemetostat, and vorinostat effectively induced apoptosis in these cells, with GD2-directed T cells also showing cytotoxicity in vivo. The ENKL-J1 cell line, therefore, provides valuable insights for developing treatments for ENKL, especially in advanced stages.
2023-12-23 | GSE251683 | GEO
Project description:Cancer stem like cells (CSLCs) acquire enhanced immune checkpoint responses to evade immune cell killing and promote tumor progression. Here we show that signal regulatory protein gamma (SIRPG) determines a small population of lung adenocarcinoma (LUAD) cancer cells for both CSLCs properties and immune evasion. SIRPGhigh population displays CSLCs properties and transmits the immune escape signal through sustaining CD47 expression to both SIRPGhigh and SIRPGlow/- tumor cells. SIRPG bridges MST1 and PP2A to facilitate MST1 dephosphorylation, resulting in Hippo/YAP activation leading to cytokine release by CSLCs, which stimulates CD47 expression in LUAD cells and consequently inhibits tumor cell phagocytosis. SIRPG promotes tumor growth and metastasis in vivo through YAP signaling. Notably, SIRPG targeting with genetic SIRPG knockdown or a SIRPG neutralization antibody inhibits CSLC phenotypes and elicits phagocytosis that suppresses tumor growth in vivo. SIRPG is upregulated in human LUAD and its overexpression predicts poor survival outcome. Thus, SIRPGhigh cells serve as CSLCs and tumor immune checkpoint initiating cells propagating the immune escape signal to the whole cancer cell populations. Our study identifies Hippo/YAP signaling as the first mechanism by which SIRPG is engaged and reveals that targeting SIRPG represents an immune and CSLC targeting strategy for lung cancer therapy.
2022-01-02 | GSE192790 | GEO