Author:
Pan Min,Zhang Yinwen,Wright William C.,Liu Xueying,Passaia Barbara,Currier Duane,Low Jonathan,Chapple Richard H.,Steele Jacob A.,Connelly Jon P.,Lu Meifen,Lee Hyeong-Min,Loughran Allister J.,Yang Lei,Abraham Brian J,Pruett-Miller Shondra M.,Freeman Burgess,Campbell George E.,Dyer Michael A.,Chen Taosheng,Stewart Elizabeth,Koo Selene,Sheppard Heather,Easton John,Geeleher Paul
Abstract
SUMMARYRetinoic 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.
Publisher
Cold Spring Harbor Laboratory