Neuroblastoma is a solid tumor that occurs in Children. When High-Risk, the disease has a poor programis. Decades ago, adding the drug retinoic acid to neuroblastoma treatment increases survival by 10–15%. However, this Effect was only Evident in post-curmotherapy consolidation after bulky primary tumors has been brought to largely been eliminated. Why retinoic acid is effective in this setting but not against primary tumors, has been spent speculated about 50 years.

St. Jude Children’s Research Hospital Scientists Resolved The Mystery in a New Study, Showing Retinoic acid uses a novel mechanism to killsized neuroblastoma. The Drug “Hijacks” a Normal Developmental Pathway to Trigger Cancer Cell Death. The findings, which have implications for future combination therapy approaches, was Published today in Nature Communications,

“We’ve come up with an explanation for a decades-long contradiction about with Senior Co-Corresponding Author Paul Geleher, Ph.D., St. Jude department of computational biology. “Retinoic acid’s activity heavily depends on the cellular microenviron.”

The cellular microenviron is the soup of chemicals, proteins and other signs 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 was very sensitive to retinoic acid,” said co-friend and co-corresponding author min paan paan, 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 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 was responsible for the drug’s activity. Genes in the BMP Pathway Had the Larget 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-friend yinwen zhang, Ph.D., St. Jude department of computational biology. Zhang Characterized How Transport Factors, The Proteins that Bind DNA to Regulate Gene Expration, LED to different Results in Highly Retinoic acid-SENSITIVE or Insensitive Neuroblastoma Cells.

“If there a lot of bmp-signaling pathway transcription factors alredy on DNA, then retinoic acid signaling combines with it to promote downstream cell death -Related –related gene experesion. Normal Embryonic Development and Neuroblastoma Cells in Certain Microenvironments, “Zhang said.

“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.”