St. Jude scientists solve mystery of how the drug retinoic acid works to treat neuroblastoma | Newswise
Using gene editing technology, the scientists uncovered the relationship between BMP signaling and retinoic acid. They assembled a group of neuroblastoma cell lines susceptible to retinoic acid, then cut out genes to find which were responsible for the drug’s activity. Genes in the BMP pathway had the largest effect while providing a plausible explanation for retinoic acid’s varying outcomes in patients.
“We found that, in neuroblastoma, BMP signaling works with retinoic acid signaling in the same way as during development,” said co-first author Yinwen Zhang, PhD, St. Jude Department of Computational Biology. Zhang characterized how transcription factors, the proteins that bind DNA to regulate gene expression, led to different results in highly retinoic acid-sensitive or insensitive neuroblastoma cells. “If there are a lot of BMP-signaling pathway transcription factors already on DNA, then retinoic acid signaling combines with it to promote downstream cell death–related gene expression. This occurs both in normal embryonic development and neuroblastoma cells in certain microenvironments.”
“We are the first to uncover such an example of ‘hijacking’ a normal embryonic developmental process preserved in cancer that we can exploit therapeutically,” Geeleher said. “Now, we can look for similar processes in other diseases to design less toxic and more effective treatment strategies.”
Authors and funding
The study’s other co-corresponding author is John Easton, of St. Jude. The study’s other authors are William Wright, Xueying Liu, Barbara Passaia, Duane Currier, Jonathan Low, Richard Chapple, Jacob Steele, Jon Connelly, Meifen Lu, Hyeong-Min Lee, Allister Loughran, Lei Yang, Brian Abraham, Shondra Pruett-Miller, Burgess Freeman III, George Campbell, Michael Dyer, Taosheng Chen, Elizabeth Stewart, Selene Koo and Heather Sheppard, all of St. Jude.
The study was supported by grants from the National Institute of General Medical Sciences (R35GM138293), National Cancer Institute (R01CA260060, P30CA021765 and P30CA021765), National Human Genome Research Institute (R00HG009679), and ALSAC, the fundraising and awareness organization of St. Jude.
