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| Status |
Public on Apr 26, 2022 |
| Title |
Epigenetic reversal of lineage plasticity enhances responsiveness to anti-GD2 therapy in neuroblastoma [ATAC-seq SK-N-AS] |
| Organism |
Homo sapiens |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
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.
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| Overall design |
SK-N-AS cells were treated for 14 days with vehicle (V) or 1 uM tazemetostat (T) in biological quadruplicate
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| Contributor(s) |
Mabe NW |
| Citation missing |
Has this study been published? Please login to update or notify GEO. |
| |
| Submission date |
Jul 20, 2021 |
| Last update date |
Apr 29, 2022 |
| Contact name |
Nathaniel Wesley Mabe |
| E-mail(s) |
nathanielw_mabe@dfci.harvard.edu
|
| Organization name |
Dana-Farber Cancer Institute
|
| Department |
Pediatric Oncology
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| Lab |
Kimberly Stegmaier
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| Street address |
450 Brookline Avenue
|
| City |
Boston |
| State/province |
Massachusetts |
| ZIP/Postal code |
02215 |
| Country |
USA |
| |
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| Platforms (1) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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| Samples (8)
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| This SubSeries is part of SuperSeries: |
| GSE180516 |
Epigenetic reversal of lineage plasticity enhances responsiveness to anti-GD2 therapy in neuroblastoma |
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| Relations |
| BioProject |
PRJNA748435 |
| SRA |
SRP329162 |
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