Related Experiment Video
Updated: Jun 29, 2025
Measurement of Natural Killer Cell-Mediated Cytotoxicity and Migration in the Context of Hepatic Tumor Cells
Published on: February 22, 2020
RBM39 degrader invigorates natural killer cells to eradicate neuroblastoma despite cancer cell plasticity
Abstract:
The cellular plasticity of neuroblastoma is defined by a mixture of two major cell states, adrenergic (ADRN) and mesenchymal (MES), which may contribute to therapy resistance. However, how neuroblastoma cells switch cellular states during therapy remains largely unknown and how to eradicate neuroblastoma regardless of their cell states is a clinical challenge. To better understand the lineage switch of neuroblastoma in chemoresistance, we comprehensively defined the transcriptomic and epigenetic map of ADRN and MES types of neuroblastomas using human and murine models treated with indisulam, a selective RBM39 degrader. We showed that cancer cells not only undergo a bidirectional switch between ADRN and MES states, but also acquire additional cellular states, reminiscent of the developmental pliancy of neural crest cells. The lineage alterations are coupled with epigenetic reprogramming and dependency switch of lineage-specific transcription factors, epigenetic modifiers and targetable kinases. Through targeting RNA splicing, indisulam induces an inflammatory tumor microenvironment and enhances anticancer activity of natural killer cells. The combination of indisulam with anti-GD2 immunotherapy results in a durable, complete response in high-risk transgenic neuroblastoma models, providing an innovative, rational therapeutic approach to eradicate tumor cells regardless of their potential to switch cell states.
Insights
Neuroblastoma cells switch states during therapy, complicating treatment. Targeting RNA splicing with indisulam and immunotherapy offers a durable response, eradicating tumors regardless of cell state.
Area of Science:
- Neuroscience
- Cancer Biology
- Genomics
Background:
- Neuroblastoma exhibits cellular plasticity, with adrenergic (ADRN) and mesenchymal (MES) states contributing to therapy resistance.
- Understanding neuroblastoma cell state switching during therapy is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the transcriptomic and epigenetic landscape of neuroblastoma cell state switching during chemoresistance.
- To elucidate the mechanisms underlying lineage alterations and epigenetic reprogramming in neuroblastoma.
- To identify novel therapeutic strategies targeting neuroblastoma plasticity.
Main Methods:
- Comprehensive transcriptomic and epigenetic mapping of ADRN and MES neuroblastoma models.
- Treatment of human and murine neuroblastoma models with indisulam, an RBM39 degrader.
- Analysis of lineage alterations, epigenetic reprogramming, and transcription factor dependencies.
Main Results:
- Neuroblastoma cells exhibit bidirectional switching between ADRN and MES states, acquiring additional developmental states.
- Lineage alterations are linked to epigenetic reprogramming and shifts in dependencies on transcription factors and kinases.
- Indisulam targets RNA splicing, promoting an inflammatory tumor microenvironment and enhancing natural killer cell activity.
Conclusions:
- Targeting RNA splicing offers a novel therapeutic strategy for neuroblastoma.
- Combination of indisulam and immunotherapy provides a rational approach to eradicate neuroblastoma irrespective of cell state plasticity.
