Bone morphogenetic protein (BMP) signaling determines neuroblastoma cell fate and sensitivity to retinoic acid
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—...
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Nature Portfolio
2025-02-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-57185-y |
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| author | 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 Paul Geeleher |
| author_facet | 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 Paul Geeleher |
| author_sort | Min Pan |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-ad29072542b34df48abed66ff9de0d49 |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-ad29072542b34df48abed66ff9de0d492025-08-20T03:03:58ZengNature PortfolioNature Communications2041-17232025-02-0116112010.1038/s41467-025-57185-yBone morphogenetic protein (BMP) signaling determines neuroblastoma cell fate and sensitivity to retinoic acidMin Pan0Yinwen Zhang1William C. Wright2Xueying Liu3Barbara Passaia4Duane Currier5Jonathan Low6Richard H. Chapple7Jacob A. Steele8Jon P. Connelly9Bensheng Ju10Emily Plyler11Meifen Lu12Allister J. Loughran13Lei Yang14Brian J. Abraham15Shondra M. Pruett-Miller16Burgess Freeman17George E. Campbell18Michael A. Dyer19Taosheng Chen20Elizabeth Stewart21Selene Koo22Heather Sheppard23John Easton24Paul Geeleher25Department of Computational Biology, St. Jude Children’s Research HospitalDepartment of Computational Biology, St. Jude Children’s Research HospitalDepartment of Computational Biology, St. Jude Children’s Research HospitalDepartment of Computational Biology, St. Jude Children’s Research HospitalDepartment of Computational Biology, St. Jude Children’s Research HospitalDepartment of Chemical Biology and Therapeutics, St. Jude Children’s Research HospitalDepartment of Chemical Biology and Therapeutics, St. Jude Children’s Research HospitalDepartment of Computational Biology, St. Jude Children’s Research HospitalDepartment of Cell and Molecular Biology, St. Jude Children’s Research HospitalDepartment of Cell and Molecular Biology, St. Jude Children’s Research HospitalDepartment of Computational Biology, St. Jude Children’s Research HospitalDepartment of Computational Biology, St. Jude Children’s Research HospitalDepartment of Pathology, St. Jude Children’s Research HospitalDepartment of Cell and Molecular Biology, St. Jude Children’s Research HospitalDepartment of Chemical Biology and Therapeutics, St. Jude Children’s Research HospitalDepartment of Computational Biology, St. Jude Children’s Research HospitalDepartment of Cell and Molecular Biology, St. Jude Children’s Research HospitalPreclinical Pharmacokinetic Shared Resource, St. Jude Children’s Research HospitalCellular Imaging Shared Resource, St. Jude Children’s Research HospitalDepartment of Developmental Neurobiology, St. Jude Children’s Research HospitalDepartment of Chemical Biology and Therapeutics, St. Jude Children’s Research HospitalCellular Imaging Shared Resource, St. Jude Children’s Research HospitalDepartment of Pathology, St. Jude Children’s Research HospitalDepartment of Pathology, St. Jude Children’s Research HospitalDepartment of Computational Biology, St. Jude Children’s Research HospitalDepartment of Computational Biology, St. Jude Children’s Research HospitalAbstract 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.https://doi.org/10.1038/s41467-025-57185-y |
| spellingShingle | 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 Paul Geeleher Bone morphogenetic protein (BMP) signaling determines neuroblastoma cell fate and sensitivity to retinoic acid Nature Communications |
| title | Bone morphogenetic protein (BMP) signaling determines neuroblastoma cell fate and sensitivity to retinoic acid |
| title_full | Bone morphogenetic protein (BMP) signaling determines neuroblastoma cell fate and sensitivity to retinoic acid |
| title_fullStr | Bone morphogenetic protein (BMP) signaling determines neuroblastoma cell fate and sensitivity to retinoic acid |
| title_full_unstemmed | Bone morphogenetic protein (BMP) signaling determines neuroblastoma cell fate and sensitivity to retinoic acid |
| title_short | Bone morphogenetic protein (BMP) signaling determines neuroblastoma cell fate and sensitivity to retinoic acid |
| title_sort | bone morphogenetic protein bmp signaling determines neuroblastoma cell fate and sensitivity to retinoic acid |
| url | https://doi.org/10.1038/s41467-025-57185-y |
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