Bone morphogenetic protein (BMP) signaling determines neuroblastoma cell fate and sensitivity to retinoic acid
Bone morphogenetic protein (BMP) signaling determines neuroblastoma cell fate and sensitivity to retinoic acid
SUMMARY 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 RA’s 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 RA’s ability to clear neuroblastoma cells specifically from the bone marrow, seemingly mimicking interactions between BMP and RA during normal development.
Connelly Jon P.、Lu Meifen、Lee Hyeong-Min、Yang Lei、Abraham Brian J、Pruett-Miller Shondra M.、Stewart Elizabeth、Pan Min、Passaia Barbara、Steele Jacob A.、Currier Duane、Geeleher Paul、Chen Taosheng、Campbell George E.、Easton John、Zhang Yinwen、Chapple Richard H.、Liu Xueying、Low Jonathan、Sheppard Heather、Dyer Michael A.、Loughran Allister J.、Freeman Burgess III、Wright William C.、Koo Selene
Department of Cell and Molecular Biology, St. Jude Children?ˉs Research Hospital||Center for Advanced Genome Engineering, St. Jude Children?ˉs Research HospitalDepartment of Pathology, St. Jude Children?ˉs Research HospitalDepartment of Computational Biology, St. Jude Children?ˉs Research HospitalDepartment of Chemical Biology and Therapeutics, St. Jude Children?ˉs Research HospitalDepartment of Computational Biology, St. Jude Children?ˉs Research HospitalDepartment of Cell and Molecular Biology, St. Jude Children?ˉs Research Hospital||Center for Advanced Genome Engineering, St. Jude Children?ˉs Research HospitalSt. Jude Children?ˉs Research HospitalDepartment of Computational Biology, St. Jude Children?ˉs Research HospitalDepartment of Computational Biology, St. Jude Children?ˉs Research HospitalDepartment of Cell and Molecular Biology, St. Jude Children?ˉs Research Hospital||Center for Advanced Genome Engineering, St. Jude Children?ˉs Research HospitalDepartment of Chemical Biology and Therapeutics, St. Jude Children?ˉs Research HospitalDepartment of Computational Biology, St. Jude Children?ˉs Research HospitalDepartment of Chemical Biology and Therapeutics, St. Jude Children?ˉs Research HospitalSt. Jude Children?ˉs Research HospitalDepartment of Computational Biology, St. Jude Children?ˉs Research HospitalDepartment of Computational Biology, St. Jude Children?ˉs Research HospitalDepartment of Computational Biology, St. Jude Children?ˉs Research HospitalDepartment of Computational Biology, St. Jude Children?ˉs Research HospitalDepartment of Chemical Biology and Therapeutics, St. Jude Children?ˉs Research HospitalDepartment of Pathology, St. Jude Children?ˉs Research HospitalDepartment of Developmental Neurobiology, St. Jude Children?ˉs Research Hospital||Howard Hughes Medical InstituteDepartment of Cell and Molecular Biology, St. Jude Children?ˉs Research Hospital||Center for Advanced Genome Engineering, St. Jude Children?ˉs Research HospitalPreclinical Pharmacokinetic Shared Resource, St. Jude Children?ˉs Research HospitalDepartment of Computational Biology, St. Jude Children?ˉs Research HospitalDepartment of Pathology, St. Jude Children?ˉs Research Hospital
肿瘤学基础医学分子生物学
Connelly Jon P.,Lu Meifen,Lee Hyeong-Min,Yang Lei,Abraham Brian J,Pruett-Miller Shondra M.,Stewart Elizabeth,Pan Min,Passaia Barbara,Steele Jacob A.,Currier Duane,Geeleher Paul,Chen Taosheng,Campbell George E.,Easton John,Zhang Yinwen,Chapple Richard H.,Liu Xueying,Low Jonathan,Sheppard Heather,Dyer Michael A.,Loughran Allister J.,Freeman Burgess III,Wright William C.,Koo Selene.Bone morphogenetic protein (BMP) signaling determines neuroblastoma cell fate and sensitivity to retinoic acid[EB/OL].(2025-03-28)[2025-05-19].https://www.biorxiv.org/content/10.1101/2024.05.09.593394.点此复制
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