St. Jude scientists discover how retinoic acid selectively kills metastatic neuroblastoma cells

Neuroblastoma is a solid tumor that occurs in children. When high-risk, the disease has a poor prognosis. Decades ago, adding the drug retinoic acid to neuroblastoma treatment increased survival by 10-15%. However, this effect was only evident in post-chemotherapy consolidation after bulky primary tumors had largely been eliminated. Why retinoic acid is effective in this setting but not against primary tumors, has been speculated about for nearly 50 years. St. Jude Children's Research Hospital scientists resolved the mystery in a new study, showing retinoic acid uses a novel mechanism to kill metastasized neuroblastoma. The drug "hijacks" a normal developmental pathway to trigger cancer cell death. The findings, which have implications for future combination therapy approaches, were published today in Nature Communications. 

We've come up with an explanation for a decades-long contradiction about why retinoic acid works in post-chemotherapy consolidation but has little impact on primary neuroblastoma tumors. Retinoic acid's activity heavily depends on the cellular microenvironment." 

Paul Geeleher, PhD, senior co-corresponding author, St. Jude Department of Computational Biology

The cellular microenvironment is the soup of chemicals, proteins and other signals that surround a cell, and which is unique to that part of the body. For example, the bone marrow microenvironment contains signals to grow blood cells and restructure bone. Metastasized neuroblastoma cells often migrate to bone marrow, where the bone morphogenetic protein (BMP) pathway signaling is highly active. The researchers showed that BMP signaling makes neuroblastoma cells much more vulnerable to retinoic acid. 

"Unexpectedly, we found that cells expressing genes from the BMP signaling pathway were very sensitive to retinoic acid," said co-first and co-corresponding author Min Pan, PhD, St. Jude Department of Computational Biology. "However, since the bone marrow microenvironment causes neuroblastoma cells there to have higher BMP activity, it neatly explained why retinoic acid is very effective at treating those cells during consolidation therapy, but not the primary tumors during up-front treatment."

Hijacking development to drive metastatic neuroblastoma cell death 

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.