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

Min Pan; Yinwen Zhang; William C. Wright; Xueying Liu; Bárbara dos Santos Passaia; Duane G. Currier; Jonathan A. Low; Richard H. Chapple; Jacob A. Steele; Jon P. Connelly; Bensheng Ju; Emily M. Plyler; Meifen Lu; Allister J. Loughran; Lei Yang; Brian J. Abraham; Shondra M. Pruett‐Miller; Burgess B. Freeman; George E. Campbell; Michael A. Dyer; Taosheng Chen; Elizabeth A. Stewart; Selene C. Koo; Heather Sheppard; John B. Easton; Paul Geeleher

doi:10.1038/s41467-025-57185-y

Cancer BiologyNature CommunicationsFeb 28, 2025

Peer-reviewed journal article

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

Min Pan iD, Yinwen Zhang iD, William C. Wright iD, Xueying Liu iD, Bárbara dos Santos Passaia iD, Duane G. Currier iD, Jonathan A. Low, Richard H. Chapple iD, Jacob A. Steele iD, Jon P. Connelly iD, Bensheng Ju iD, Emily M. Plyler iD, Meifen Lu iD, Allister J. Loughran iD, Lei Yang iD, Brian J. Abraham iD, Shondra M. Pruett‐Miller iD, Burgess B. Freeman iD, George E. Campbell iD, Michael A. Dyer iD, Taosheng Chen iD, Elizabeth A. Stewart iD, Selene C. Koo iD, Heather Sheppard iD, John B. Easton iD, Paul Geeleher iD

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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 consolidation therapy--a discrepancy that has never been explained. To investigate this, we treated a large cohort of neuroblastoma cell lines with RA and observed that the most RA-sensitive cells predominantly undergo apoptosis or senescence, rather than differentiation. We conducted genome-wide CRISPR knockout screens under RA treatment, which identified BMP signaling as controlling the apoptosis/senescence vs differentiation cell fate decision and determining RAs overall potency. We then discovered that BMP signaling activity is markedly higher in neuroblastoma patient samples at bone marrow metastatic sites, providing a plausible explanation for RAs ability to clear neuroblastoma cells specifically from the bone marrow, seemingly mimicking interactions between BMP and RA during normal development.