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<p>The cellular plasticity of neuroblastoma is defined by a mixture of two major cell states, adrenergic and mesenchymal, 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 its cell state is a clinical challenge. To better understand the cellular plasticity of neuroblastoma in chemoresistance, we define the transcriptomic and epigenetic map of adrenergic and mesenchymal types of neuroblastomas using human and murine models treated with indisulam, a selective RBM39 degrader. We show that cancer cells not only undergo a bidirectional switch between adrenergic and mesenchymal states, but also acquire additional cellular states, reminiscent of the developmental pliancy of neural crest cells. These cell state alterations are coupled with epigenetic reprogramming and dependency switching of cell state–specific transcription factors, epigenetic modifiers, and targetable kinases. Through targeting RNA splicing, indisulam induces an inflammatory tumor microenvironment and enhances the 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.</p>

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RBM39 degrader invigorates innate immunity to eradicate neuroblastoma despite cancer cell plasticity

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月17日

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  • Shivendra Singh,
  • Jie Fang,
  • Hongjian Jin,
  • Lee-Ann Van De Velde,
  • Andrew Cortes,
  • Jiani Chen,
  • Sivaraman Natarajan,
  • Evon Poon,
  • Qiong Wu,
  • Christopher L. Morton,
  • Mary A. Woolard,
  • Waise Quarni,
  • Jacob A. Steele,
  • Jon P. Connelly,
  • Liusheng He,
  • Rebecca Thorne,
  • Gregory Turner,
  • Thomas Confer,
  • Melissa Johnson,
  • William V. Caufield,
  • Burgess B. Freeman III,
  • Timothy Lockey,
  • Andrew J. Murphy,
  • Peter J. Murray,
  • Takashi Owa,
  • Shondra M. Pruett-Miller,
  • Ruoning Wang,
  • Louis Chesler,
  • Julie R. Park,
  • Andrew M. Davidoff,
  • John Easton,
  • Xiang Chen,
  • Paul G. Thomas,
  • Jun Yang

摘要

The cellular plasticity of neuroblastoma is defined by a mixture of two major cell states, adrenergic and mesenchymal, 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 its cell state is a clinical challenge. To better understand the cellular plasticity of neuroblastoma in chemoresistance, we define the transcriptomic and epigenetic map of adrenergic and mesenchymal types of neuroblastomas using human and murine models treated with indisulam, a selective RBM39 degrader. We show that cancer cells not only undergo a bidirectional switch between adrenergic and mesenchymal states, but also acquire additional cellular states, reminiscent of the developmental pliancy of neural crest cells. These cell state alterations are coupled with epigenetic reprogramming and dependency switching of cell state–specific transcription factors, epigenetic modifiers, and targetable kinases. Through targeting RNA splicing, indisulam induces an inflammatory tumor microenvironment and enhances the 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.