Neuroblastoma is a solid tumor that occurs in children. When high risk is, the disease has a bad prognosis. Decades ago, adding drug retino acid to neuroblastoma treatment increased survival by 10-15%. However, this effect was only evident in the consolidation posterior to loophorapy after bulky primary tumors had been largely eliminated. It has been speculated why retinoic acid has been speculated in this environment but not against primary tumors for almost 50 years. St. Jude Children’s Research Hospital scientists resolved the mystery in a new study, which shows that retinoic acid uses a novel mechanism to kill metastase neuroblastoma. The medicine “kidnaps” a normal development route to trigger the death of cancer cells. The findings, which have implications for future combination therapy approaches, were published in Nature communications.
“We occurred to us an explanation during a contradiction of decades about why retinoic acid works in the consolidation posterior to loophorapy, but has little impact on primary neuroblastoma tumors,” said Senior author Paul Geeleher, PHD, Department of St. Jude Computational Biology. “The activity of retinoic acid depends largely on the cell microenvironment.”
The cell microenvironment is the soup of chemicals, proteins and other signals that surround a cell, and that is exclusive to that part of the body. For example, bone marrow microenvironment contains signals to grow blood cells and restructure bone. Metastasis neuroblastoma cells often migrate to the bone marrow, where bone morphogenetic protein signaling (BMP) is highly active. The researchers showed that BMP signage causes neuroblastoma cells to be much more vulnerable to retinoic acid.
“Unexpectedly, we find that cells that express genes of the BMP signaling route were very sensitive to retinoic acid,” said the co-director and the corresponding author min Pan, PHD, Department of Computational Biology of St. Jude. “However, since the bone marrow microenvironment makes neuroblastoma cells there a greater BMP activity, carefully explained why retinoic acid is very effective in treating these cells during consolidation therapy, but not primary tumors during treatment up.”
Kidnapping development to boost the death of metastatic neuroblastoma cells
Using gene editing technology, scientists discovered the relationship between BMP signaling and retinoic acid. They assembled a group of neuroblastoma cell lines susceptible to retinoic acid, then cut genes to find which were responsible for the drug activity. The genes on the BMP road had the greatest effect in the time they provided a plausible explanation for the different results of retinoic acid in patients.
“We discover that, in the neuroblastoma, the signaling of BMP works with retinoic acid signage in the same way as during development,” said author Yinwen Zhang, PHD, Department of Computational Biology of St. Jude. Zhang characterized how transcription factors, proteins that bind to DNA to regulate gene expression, led to different results in highly sensitive neuroblastoma cells to retinoic or insensitive acid. “If there are already many transcription factors of the BMP signaling route in the DNA, then the retinoic acid signage is combined to promote gene expression related to cell death downstream. This occurs both in normal embryonic development and in neuroblastoma cells in certain microambientes.”
“We are the first to discover such an example of ‘kidnapping’ a normal embryonic development 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.”