Bone morphogenetic protein (BMP) signaling determines neuroblastoma cell fate and sensitivity to retinoic acid
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.
Authors
- Taosheng Chen (ORCID: https://orcid.org/0000-0001-6420-3809)
- Jacob Steele (ORCID: https://orcid.org/0000-0001-9924-2226)
- Shondra M. Pruett‐Miller (ORCID: https://orcid.org/0000-0002-3793-585X)
- Heather Sheppard (ORCID: https://orcid.org/0000-0002-9623-2812)
- Michael A. Dyer
- Duane Currier (ORCID: https://orcid.org/0000-0002-0123-0233)
- John Easton (ORCID: https://orcid.org/0000-0003-4503-6608)
- Lei Yang (ORCID: https://orcid.org/0000-0002-3060-0790)
- Brian J. Abraham (ORCID: https://orcid.org/0000-0001-8085-3027)
- Jon P. Connelly (ORCID: https://orcid.org/0000-0002-5564-1775)
- Yinwen Zhang (ORCID: https://orcid.org/0000-0001-8776-6823)
- Burgess B. Freeman (ORCID: https://orcid.org/0000-0003-2174-5119)
- Richard H. Chapple (ORCID: https://orcid.org/0000-0002-0375-2043)
- Paul Geeleher (ORCID: https://orcid.org/0000-0002-5128-0087)
- Xueying Liu
- Selene C. Koo (ORCID: https://orcid.org/0000-0001-8459-2469)
- Meifen Lu
- William C. Wright (ORCID: https://orcid.org/0000-0002-2274-9966)
- George E. Campbell (ORCID: https://orcid.org/0000-0003-1288-2576)
- Allister J. Loughran (ORCID: https://orcid.org/0000-0002-6564-5526)
- Bárbara dos Santos Passaia (ORCID: https://orcid.org/0000-0001-8933-2586)
- Emily M. Plyler (ORCID: https://orcid.org/0000-0003-2642-1674)
- Jonathan Low
- Elizabeth Stewart (ORCID: https://orcid.org/0000-0001-8005-0427)
- Min Pan (ORCID: https://orcid.org/0000-0002-9338-8491)
- Bensheng Ju
Institutions
- St. Jude Children's Research Hospital (US)
- Howard Hughes Medical Institute (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-02-28
- DOI
- https://doi.org/10.1038/s41467-025-57185-y
- Citations
- 3
- Primary Topic
- Neuroblastoma Research and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 4.17
Funders
- National Institute of General Medical Sciences