2. Academic Validation
  3. Bone morphogenetic protein (BMP) signaling determines neuroblastoma cell fate and sensitivity to retinoic acid

Bone morphogenetic protein (BMP) signaling determines neuroblastoma cell fate and sensitivity to retinoic acid

  • Nat Commun. 2025 Feb 28;16(1):2036. doi: 10.1038/s41467-025-57185-y.
Min Pan # 1,  Yinwen Zhang # 2,  William C Wright 2,  Xueying Liu 2,  Barbara Passaia 2,  Duane Currier 3,  Jonathan Low 3,  Richard H Chapple 2,  Jacob A Steele 4 5,  Jon P Connelly 4 5,  Bensheng Ju 2,  Emily Plyler 2,  Meifen Lu 6,  Allister J Loughran 4 5,  Lei Yang 3,  Brian J Abraham 2,  Shondra M Pruett-Miller 4 5,  Burgess Freeman 3rd 7,  George E Campbell 8,  Michael A Dyer 9 10,  Taosheng Chen 3,  Elizabeth Stewart 8,  Selene Koo 6,  Heather Sheppard 6,  John Easton 11,  Paul Geeleher 12
Affiliations

Affiliations

  • 1 Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA. min.pan@stjude.org.
  • 2 Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
  • 3 Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
  • 4 Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
  • 5 Center for Advanced Genome Engineering, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
  • 6 Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
  • 7 Preclinical Pharmacokinetic Shared Resource, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
  • 8 Cellular Imaging Shared Resource, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
  • 9 Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
  • 10 Howard Hughes Medical Institute, Chevy Chase, MD, 20815, USA.
  • 11 Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA. john.easton@stjude.org.
  • 12 Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA. paul.geeleher@stjude.org.
  • # Contributed equally.
PMID: 40021625 DOI: 10.1038/s41467-025-57185-y
Abstract

Retinoic acid (RA) is a standard-of-care neuroblastoma drug thought to be effective by inducing differentiation. Curiously, RA has little effect on primary human tumors during upfront treatment but can eliminate neuroblastoma cells from the bone marrow during post-chemo maintenance therapy-a discrepancy that has never been explained. To investigate this, we treat a large cohort of neuroblastoma cell lines with RA and observe that the most RA-sensitive cells predominantly undergo Apoptosis or senescence, rather than differentiation. We conduct genome-wide CRISPR knockout screens under RA treatment, which identify bone morphogenic protein (BMP) signaling as controlling the Apoptosis/senescence vs differentiation cell fate decision and determining RA's overall potency. We then discover that BMP signaling activity is markedly higher in neuroblastoma patient samples at bone marrow metastatic sites, providing a plausible explanation for RA's ability to clear neuroblastoma cells specifically from the bone marrow, by seemingly mimicking interactions between BMP and RA during normal development.

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