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

Author

Listed:
  • Min Pan

    (St. Jude Children’s Research Hospital)

  • Yinwen Zhang

    (St. Jude Children’s Research Hospital)

  • William C. Wright

    (St. Jude Children’s Research Hospital)

  • Xueying Liu

    (St. Jude Children’s Research Hospital)

  • Barbara Passaia

    (St. Jude Children’s Research Hospital)

  • Duane Currier

    (St. Jude Children’s Research Hospital)

  • Jonathan Low

    (St. Jude Children’s Research Hospital)

  • Richard H. Chapple

    (St. Jude Children’s Research Hospital)

  • Jacob A. Steele

    (St. Jude Children’s Research Hospital
    St. Jude Children’s Research Hospital)

  • Jon P. Connelly

    (St. Jude Children’s Research Hospital
    St. Jude Children’s Research Hospital)

  • Bensheng Ju

    (St. Jude Children’s Research Hospital)

  • Emily Plyler

    (St. Jude Children’s Research Hospital)

  • Meifen Lu

    (St. Jude Children’s Research Hospital)

  • Allister J. Loughran

    (St. Jude Children’s Research Hospital
    St. Jude Children’s Research Hospital)

  • Lei Yang

    (St. Jude Children’s Research Hospital)

  • Brian J. Abraham

    (St. Jude Children’s Research Hospital)

  • Shondra M. Pruett-Miller

    (St. Jude Children’s Research Hospital
    St. Jude Children’s Research Hospital)

  • Burgess Freeman

    (St. Jude Children’s Research Hospital)

  • George E. Campbell

    (St. Jude Children’s Research Hospital)

  • Michael A. Dyer

    (St. Jude Children’s Research Hospital
    Howard Hughes Medical Institute)

  • Taosheng Chen

    (St. Jude Children’s Research Hospital)

  • Elizabeth Stewart

    (St. Jude Children’s Research Hospital)

  • Selene Koo

    (St. Jude Children’s Research Hospital)

  • Heather Sheppard

    (St. Jude Children’s Research Hospital)

  • John Easton

    (St. Jude Children’s Research Hospital)

  • Paul Geeleher

    (St. Jude Children’s Research Hospital)

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.

Suggested Citation

  • Min Pan & Yinwen Zhang & William C. Wright & Xueying Liu & Barbara Passaia & Duane Currier & Jonathan Low & Richard H. Chapple & Jacob A. Steele & Jon P. Connelly & Bensheng Ju & Emily Plyler & Meifen, 2025. "Bone morphogenetic protein (BMP) signaling determines neuroblastoma cell fate and sensitivity to retinoic acid," Nature Communications, Nature, vol. 16(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57185-y
    DOI: 10.1038/s41467-025-57185-y
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    as
    1. Min Pan & William C. Wright & Richard H. Chapple & Asif Zubair & Manbir Sandhu & Jake E. Batchelder & Brandt C. Huddle & Jonathan Low & Kaley B. Blankenship & Yingzhe Wang & Brittney Gordon & Payton A, 2021. "The chemotherapeutic CX-5461 primarily targets TOP2B and exhibits selective activity in high-risk neuroblastoma," Nature Communications, Nature, vol. 12(1), pages 1-20, December.
    2. Hyeong-Min Lee & William C. Wright & Min Pan & Jonathan Low & Duane Currier & Jie Fang & Shivendra Singh & Stephanie Nance & Ian Delahunty & Yuna Kim & Richard H. Chapple & Yinwen Zhang & Xueying Liu , 2023. "A CRISPR-drug perturbational map for identifying compounds to combine with commonly used chemotherapeutics," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    3. Samuel W. Brady & Yanling Liu & Xiaotu Ma & Alexander M. Gout & Kohei Hagiwara & Xin Zhou & Jian Wang & Michael Macias & Xiaolong Chen & John Easton & Heather L. Mulder & Michael Rusch & Lu Wang & Joy, 2020. "Pan-neuroblastoma analysis reveals age- and signature-associated driver alterations," Nature Communications, Nature, vol. 11(1), pages 1-13, December.
    4. Irfete S. Fetahu & Wolfgang Esser-Skala & Rohit Dnyansagar & Samuel Sindelar & Fikret Rifatbegovic & Andrea Bileck & Lukas Skos & Eva Bozsaky & Daria Lazic & Lisa Shaw & Marcus Tötzl & Dora Tarlungean, 2023. "Single-cell transcriptomics and epigenomics unravel the role of monocytes in neuroblastoma bone marrow metastasis," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
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