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Eradicating neuroblastomas by an RBM39 degrader in combination with anti-GD2 immunotherapy regardless of cancer cell state alterations

ABSTRACT: Eradicating neuroblastomas by an RBM39 degrader in combination with anti-GD2 immunotherapy regardless of cancer cell state alterations

PROVIDER: PRJNA1055918 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR27329607_1.fastq.gz	Fastqsanger.gz
	SRR27329607_2.fastq.gz	Fastqsanger.gz
	SRR27329608_1.fastq.gz	Fastqsanger.gz
	SRR27329608_2.fastq.gz	Fastqsanger.gz
	SRR27329609_1.fastq.gz	Fastqsanger.gz

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Eradicating neuroblastomas by an RBM39 degrader in combination with anti-GD2 immunotherapy regardless of cancer cell state alterations [CUT&Tag]

Project description:Eradicating neuroblastomas by an RBM39 degrader in combination with anti-GD2 immunotherapy regardless of cancer cell state alterations [CUT&Tag]

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Eradicating neuroblastomas by an RBM39 degrader in combination with anti-GD2 immunotherapy regardless of cancer cell state alterations [RNA-seq]

Project description:Eradicating neuroblastomas by an RBM39 degrader in combination with anti-GD2 immunotherapy regardless of cancer cell state alterations [RNA-seq]

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Eradicating neuroblastomas by an RBM39 degrader in combination with anti-GD2 immunotherapy regardless of cancer cell state alterations [RNA-seq]

Project description:The lineage plasticity of neuroblastoma cells is defined by a mixture of two major cell states, adrenergic (ADRN) and mesenchymal (MES), which presumably contributes to therapy resistance. However, how the neuroblastoma cells switch their cell states during therapy remains largely unknown and how to eradicate neuroblastoma cells regardless of their cell state alterations is a clinical challenge. By using four distinct human and murine neuroblastoma models treated with indisulam, a molecular glue drug serving as a selective RBM39 degrader, we show that cancer cells not only can undergo bidirectional switch of ADRN and MES cell states, but also can acquire additional cell states of melanoma and Schwann cell progenitors, reminiscent of the cellular pliancy of neural crest cells. The lineage alterations of neuroblastoma cells are coupled with epigenetic changes and dependency switch of lineage-specific transcription factors. Nevertheless, indisulam treatment induces an inflamed tumor microenvironment leading to an immune cell infiltration. The combination of indisulam with anti-GD2 monoclonal immunotherapy results in a durable complete response in transgenic neuroblastoma models driven by MYCN and ALK mutant oncogenes, providing a therapeutic rationale to eradicate tumor cells even when they acquire alternative cell lineage(s) in response to treatment.

2025-06-05 | GSE251918 | GEO

Eradicating neuroblastomas by an RBM39 degrader in combination with anti-GD2 immunotherapy regardless of cancer cell state alterations [CUT&Tag]

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Eradicating neuroblastomas by an RBM39 degrader in combination with anti-GD2 immunotherapy regardless of cancer cell state alterations

Project description:This SuperSeries is composed of the SubSeries listed below.

2025-06-05 | GSE251920 | GEO

Ganglioside GD2 identifies Breast Cancer Stem Cells: Targeting GD3 Synthase Inhibits GD2 Expression and Tumor Growth

Project description:We FACS sorted Ras-transformed human mammary epithelial cells (HMLER cells) into GD2+ and GD2- as well as CD44high/CD24low and CD44low/Cd24highcells and comapred the four different population by array. We FACS sorted Ras-transformed human mammary epithelial cells (HMLER cells) into GD2+ and GD2- as well as CD44high/CD24low and CD44low/Cd24highcells and comapred the four different population by array.

2012-04-12 | E-GEOD-36643 | biostudies-arrayexpress

Epigenetic reversal of lineage plasticity enhances responsiveness to anti-GD2 therapy in neuroblastoma [ChIP-Seq]

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.

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Epigenetic reversal of lineage plasticity enhances responsiveness to anti-GD2 therapy in neuroblastoma [RNA-seq kelly cells]

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Epigenetic reversal of lineage plasticity enhances responsiveness to anti-GD2 therapy in neuroblastoma [ATAC-seq SK-N-AS]

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Epigenetic reversal of lineage plasticity enhances responsiveness to anti-GD2 therapy in neuroblastoma [RNA-seq SKNBE2 or KPNYN]

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