We want to check chromotin conformation changes and chromotin accesiblility. We also want to compare gene profile with and without indusilam resistant tumors in mouse genetic model
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE293865 | GEO | 2025/06/05
REPOSITORIES: GEO
Similar Datasets
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
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 | GSE251915 | GEO
Project description:Neuroblastoma accounts for 15% cancer related deaths in children, largely due to the disease relapse after multimodal therapy. Understanding the mechanism by which cancer cells acquire therapy resistance is critical to develop therapies for eradicating all cancer cells. Neuroblastoma are composed of two major cell states, adrenergic (ADRN) and mesenchymal (MES), which are presumed to interconvert and contribute to therapy resistance. To better understand the cell plasticity of neuroblastoma in chemoresistance, we repeatedly treated human and murine neuroblastoma models with indisulam, a molecular glue drug that selectively degrades RBM39, a splicing factor critical to neuroblastoma cell survival. until these tumors developed full resistance. We then generated transcriptomic data, ATAC-seq data, CUT&Tag for H3K27Ac from these tumors, and defined their cell state features. These datasets provided a comprehensive transcriptomic and epigenetic profiling on ADRN and MES neuroblastoma cells after they developed therapy resistance. Here, we provided a detailed description of these unique datasets to facilitate their reusing. We anticipate that these datasets are useful resources to understand the role of cell lineage switching in therapy resistance.
2025-06-06 | GSE299170 | GEO
Project description:Neuroblastoma accounts for 15% cancer related deaths in children, largely due to the disease relapse after multimodal therapy. Understanding the mechanism by which cancer cells acquire therapy resistance is critical to develop therapies for eradicating all cancer cells. Neuroblastoma are composed of two major cell states, adrenergic (ADRN) and mesenchymal (MES), which are presumed to interconvert and contribute to therapy resistance. To better understand the cell plasticity of neuroblastoma in chemoresistance, we repeatedly treated human and murine neuroblastoma models with indisulam, a molecular glue drug that selectively degrades RBM39, a splicing factor critical to neuroblastoma cell survival. until these tumors developed full resistance. We then generated transcriptomic data, ATAC-seq data, CUT&Tag for H3K27Ac from these tumors, and defined their cell state features. These datasets provided a comprehensive transcriptomic and epigenetic profiling on ADRN and MES neuroblastoma cells after they developed therapy resistance. Here, we provided a detailed description of these unique datasets to facilitate their reusing. We anticipate that these datasets are useful resources to understand the role of cell lineage switching in therapy resistance.
2025-06-06 | GSE299169 | GEO
Project description:Neuroblastoma accounts for 15% cancer related deaths in children, largely due to the disease relapse after multimodal therapy. Understanding the mechanism by which cancer cells acquire therapy resistance is critical to develop therapies for eradicating all cancer cells. Neuroblastoma are composed of two major cell states, adrenergic (ADRN) and mesenchymal (MES), which are presumed to interconvert and contribute to therapy resistance. To better understand the cell plasticity of neuroblastoma in chemoresistance, we repeatedly treated human and murine neuroblastoma models with indisulam, a molecular glue drug that selectively degrades RBM39, a splicing factor critical to neuroblastoma cell survival. until these tumors developed full resistance. We then generated transcriptomic data, ATAC-seq data, CUT&Tag for H3K27Ac from these tumors, and defined their cell state features. These datasets provided a comprehensive transcriptomic and epigenetic profiling on ADRN and MES neuroblastoma cells after they developed therapy resistance. Here, we provided a detailed description of these unique datasets to facilitate their reusing. We anticipate that these datasets are useful resources to understand the role of cell lineage switching in therapy resistance.
2025-06-06 | GSE299173 | GEO
Project description:Indisulam selectively bridges splicing factor RBM39 to DCAF15 for proteasomal degradation. However, clinical trials indicate that patient stratification based upon the mechanism of action of indisulam may be required to achieve the best response. Here we show that neuroblastoma, a MYC-driven cancer characterized by splicing dysregulation, requires RBM39 for survival, expresses high levels of DCAF15 among different solid tumor lineages, and is the most sensitive cancer lineage to indisulam that achieves therapeutic effect by specifically targeting RBM39 in neuroblastoma. Genetic depletion or proteasomal degradation of RBM39 by indisulam induces drastic splicing event changes in neuroblastoma cells. Through specifically targeting RBM39, indisulam induces exceptional tumor response in multiple high-risk neuroblastoma models. Collectively we demonstrate that high RBM39 dependency and high-level expression of DCAF15 provide indisulam a more efficacious therapeutic window to treating high-risk neuroblastoma.
2021-11-24 | GSE164504 | GEO
Project description:Indisulam selectively bridges splicing factor RBM39 to DCAF15 for proteasomal degradation. However, clinical trials indicate that patient stratification based upon the mechanism of action of indisulam may be required to achieve the best response. Here we show that neuroblastoma, a MYC-driven cancer characterized by splicing dysregulation, requires RBM39 for survival, expresses high levels of DCAF15 among different solid tumor lineages, and is the most sensitive cancer lineage to indisulam that achieves therapeutic effect by specifically targeting RBM39 in neuroblastoma. Genetic depletion or proteasomal degradation of RBM39 by indisulam induces drastic splicing event changes in neuroblastoma cells. Through specifically targeting RBM39, indisulam induces exceptional tumor response in multiple high-risk neuroblastoma models. Collectively we demonstrate that high RBM39 dependency and high-level expression of DCAF15 provide indisulam a more efficacious therapeutic window to treating high-risk neuroblastoma.
2021-11-24 | GSE164505 | GEO
Project description:Neuroblastoma is the most common solid tumour in childhood. Prognosis remains poor for high risk cases despite the use of multimodal treatment, highlighting the urgent need for novel therapeutic strategies. Analysis of cell line drug sensitivity data suggested that among solid tumours neuroblastoma could be the most sensitive to treatment with indisulam (E7070). Indisulam is a clinical aryl sulphonamide and selective promoter of DCAF15-E3-ubiquitin ligase dependent degradation of the RNA splicing factor and transcriptional coactivator RBM39. Here, we demonstrate for the first time that indisulam is highly efficacious in vitro and in vivo in experimental models of neuroblastoma. Indisulam induced rapid depletion of RBM39, accumulation of splicing errors in mRNA and growth inhibition in a DCAF15-dependent manner. Global analysis of protein and RNA alterations in IMR32 cells demonstrated a significant overlap between mis-spliced RNA and decrease in protein levels. Pathway analysis indicated an enrichment for genes involved in cell cycle and one-carbon metabolism, including CDK4 and TYMS. Finally, indisulam induces mitochondrial dysfunction, metabolome perturbations, alterations to redox balance and NAD/NADH ratio in vitro. Metabolic changes were validated in IMR32 xenografts in vivo. Collectively, our data suggest that high-risk neuroblastomas, which are frequently MYCN/MYC-driven, may be particularly susceptible to the dual targeting of metabolism and RNA splicing with anticancer sulfonamides such as indisulam
2021-12-30 | GSE160446 | GEO
Project description:Acute megakaryoblastic leukemia (AMKL) is a subtype of acute myeloid leukemia with clinical heterogeneity. The poor prognosis of AMKL means that new therapies need to be developed to treat this disease. Studies have shown that the dysregulation of alternative splicing is associated with the occurrence and development of AMKL and the increase of chemotherapy resistance. indisulam, as a synthetic aryl sulfonamide, can effectively treat solid tumors by targeting the splicing factor RBM39. However, the effects of indisulam on AMKL and the underlying molecular mechanisms remain to be thoroughly investigated. We first screened AMKL for indisulam susceptibility in a public drug-susceptibility database. The results showed that AMKL was more sensitive to insulin than other tumor types. We then treated human AMKL cell lines (CMK, MEG01 and M07e) with indisulam to evaluate its efficacy and investigate its molecular targets. The results suggest that indisulam induces RBM39 degradation and inhibits tumor growth in a dose-dependent manner. RNA-seq and proteomic analyses revealed that indisulam selectively degraded RBM39 and resulted in mis-splicing of the transcription factor ZMYND8, which maintains AML survival and proliferation. We knocked down ZMYND8 and confirmed the critical role of ZMYND8 in maintaining AMKL survival and proliferation. In addition, we verified that the anti-tumor effect of indisulam on AMKL was DCAF15 dependent. By targeting DCAF15 using CRISPR/Cas9 system, we confirmed the DCAF15-dependent effect of indisulam in both in vivo and in vitro models. Taken together, our study suggests that indisulam has promising therapeutic potential for AMKL by specifically targeting the splicing factor RBM39 and is dependent on the expression of DCAF15. In addition, our study identified ZMYND8 as a novel downstream regulator of RBM39 and the RBM39-ZMYND8 axis is important for AMKL survival and proliferation.
2025-04-23 | GSE266925 | GEO
Project description:Indisulam is an abandoned drug that acts as a molecular glue, inducing degradation of splicing factor RBM39 through interaction with CRL4DCAF15. We generated spontaneoulsy indisulam-resistant Panc10.05 cells and studied their response to indisulam.
2022-04-09 | GSE200281 | GEO