Scientists have discovered why retinoic acid selectively kills metastatic neuroblastoma cells

Neuroblastoma is a solid tumor that occurs in children. In high-risk disease, the prognosis is poor. Decades ago, the addition of retinoic acid to neuroblastoma treatment increased survival by 10-15%. However, this effect was only seen with consolidation after chemotherapy, after voluminous primary tumors had been almost completely removed. As to why retinoic acid is effective in this case, but not against primary tumors, scientists have been debating for nearly 50 years. Scientists at St. Jude Children’s Research Hospital have solved this mystery in a new study, showing that retinoic acid uses a unique mechanism to kill metastasized neuroblastoma. The drug “hijacks” the normal developmental pathway to induce cancer cell death. The findings, which have implications for future approaches to combination therapies, are published in Nature Communications.

“We have found an explanation for the decades-long controversy as to why retinoic acid works in consolidation after chemotherapy but has little effect on primary neuroblastoma tumors. Retinoic acid activity is largely dependent on the cellular microenvironment.”

Paul Geeleher, PhD, Senior Co-Author, Department of Computational Biology, St. Jude Hospital

The cellular microenvironment is the combination of chemicals, proteins, and other signals that surround a cell and that are unique to that part of the body. For example, the bone marrow microenvironment contains signals for blood cell growth and bone restructuring. Metastatic neuroblastoma cells often migrate to the bone marrow, where the bone morphogenetic protein (BMP) signaling pathway is very 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 are very sensitive to retinoic acid,” said paper co-author Min Pan, PhD, of the Department of Computational Biology at St. Jude Hospital. – However, because the bone marrow microenvironment causes neuroblastoma cells to have increased BMP activity, this explains why retinoic acid is very effective on these cells during consolidation therapy but not on primary tumors during initial treatment.”

Developmental hijacking to ensure cell death of metastatic neuroblastoma cells

Using gene editing technology, the scientists identified a link between BMP signaling and retinoic acid. They assembled a group of neuroblastoma cell lines susceptible to retinoic acid and then cut out genes to find those responsible for the drug’s activity. The genes associated with the BMP pathway had the greatest impact, providing a plausible explanation for the varying results of retinoic acid in patients.

The scientists found that in neuroblastoma, BMP signaling interacts with retinoic acid signaling in the same way it does during development. They also characterized how transcription factors – proteins that bind DNA to regulate gene expression – lead to different outcomes in neuroblastoma cells sensitive or insensitive to retinoic acid.

If there are already a large number of transcription factors of the BMP-signaling pathway on the DNA, retinoic acid signals combine with them and promote the expression of genes associated with cell death. This occurs both during normal embryonic development and in neuroblastoma cells in certain microenvironments.

“We have for the first time discovered an example of ‘hijacking’ of a normal embryonic developmental process conserved in cancer that we can exploit for therapeutic purposes,” says Gileher. ‘We can now look for similar processes in other diseases to develop less toxic and more effective treatment strategies.”

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Published: 05.03.2025

Updated: 04.03.2025

Medical author, Medical editor:

Stepan Yuk

Medical expert:

PhD. Olexandr Voznyak