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

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 Lu, Allister J. Loughran, Lei Yang, Brian J. Abraham, Shondra M. Pruett-Miller, Burgess Freeman, George E. Campbell, Michael A. Dyer, Taosheng Chen, Elizabeth Stewart, Selene Koo, Heather Sheppard, John Easton () and Paul Geeleher ()
Additional contact information
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
Jon P. Connelly: 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
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
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
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

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-57185-y

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