2. Academic Validation
  3. RBM39 degrader invigorates innate immunity to eradicate neuroblastoma despite cancer cell plasticity

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

  • Nat Commun. 2025 Sep 17;16(1):8287. doi: 10.1038/s41467-025-63979-x.
Shivendra Singh # 1,  Jie Fang # 1,  Hongjian Jin # 2,  Lee-Ann Van De Velde # 3,  Andrew Cortes # 1,  Jiani Chen 4,  Sivaraman Natarajan 4,  Evon Poon 5,  Qiong Wu 1,  Christopher L Morton 1,  Mary A Woolard 1,  Waise Quarni 1,  Jacob A Steele 6,  Jon P Connelly 6,  Liusheng He 3,  Rebecca Thorne 7,  Gregory Turner 7,  Thomas Confer 7,  Melissa Johnson 7,  William V Caufield 8,  Burgess B Freeman 3rd 8,  Timothy Lockey 9,  Andrew J Murphy 1,  Peter J Murray 10,  Takashi Owa 11,  Shondra M Pruett-Miller 6,  Ruoning Wang 12,  Louis Chesler 5,  Julie R Park 13,  Andrew M Davidoff 1 14 15,  John Easton 4,  Xiang Chen 4,  Paul G Thomas 3,  Jun Yang 16 17 18
Affiliations

Affiliations

  • 1 Department of Surgery, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • 2 Center for Applied Bioinformatics, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • 3 Department of Host Microbe Interactions, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • 4 Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • 5 Division of Clinical Studies, The Institute of Cancer Research, London, UK.
  • 6 Center for Advanced Genome Engineering (CAGE) and Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • 7 Center for In Vivo Imaging & Therapeutics, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • 8 Preclinical Pharmacokinetics Shared Resource, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • 9 Therapeutics Production and Quality, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • 10 Max Planck Institute of Biochemistry, Martinsried, Germany.
  • 11 Eisai Inc., Nutley, NJ, USA.
  • 12 Center for Childhood Cancer Research, Abigail Wexner Research Institute, Nationwide Children's Hospital, The Ohio State University, Columbus, OH, USA.
  • 13 Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • 14 Department of Surgery, The University of Tennessee Health Science Center, Memphis, TN, USA.
  • 15 Department of Pathology, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN, USA.
  • 16 Department of Surgery, St. Jude Children's Research Hospital, Memphis, TN, USA. Jun.Yang2@stjude.org.
  • 17 Department of Pathology, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN, USA. Jun.Yang2@stjude.org.
  • 18 College of Graduate Health Sciences, University of Tennessee Health Science Center, Memphis, TN, USA. Jun.Yang2@stjude.org.
  • # Contributed equally.
PMID: 40962798 DOI: 10.1038/s41467-025-63979-x
Abstract

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.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z