(L to R) Co-first and co-corresponding creator Min Pan, Ph.D., co-first creator Yinwen Zhang, Ph.D., St. Jude Division of Computational Biology, co-corresponding creator John Easton, Ph.D., St. Jude Computational Biology Genomics Laboratory director and senior co-corresponding creator Paul Geeleher, Ph.D., St. Jude Division of Computational Biology. Credit score: St. Jude Youngsters’s Analysis Hospital
Neuroblastoma is a stable tumor that happens in kids. When high-risk, the illness has a poor prognosis. Many years in the past, including the drug retinoic acid to neuroblastoma therapy elevated survival by 10–15%. Nevertheless, this impact was solely evident in post-chemotherapy consolidation after cumbersome major tumors had largely been eradicated. Why retinoic acid is efficient on this setting however not in opposition to major tumors, has been speculated about for practically 50 years.
St. Jude Youngsters’s Analysis Hospital scientists resolved the thriller in a brand new examine, exhibiting retinoic acid makes use of a novel mechanism to kill metastasized neuroblastoma. The drug “hijacks” a standard developmental pathway to set off most cancers cell demise. The findings, which have implications for future mixture remedy approaches, have been revealed at the moment 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,” stated senior co-corresponding creator Paul Geeleher, Ph.D., St. Jude Division of Computational Biology. “Retinoic acid’s activity heavily depends on the cellular microenvironment.”
The mobile microenvironment is the soup of chemical substances, proteins and different alerts that encompass a cell, and which is exclusive to that a part of the physique. For instance, the bone marrow microenvironment accommodates alerts to develop blood cells and restructure bone. Metastasized neuroblastoma cells typically migrate to bone marrow, the place the bone morphogenetic protein (BMP) pathway signaling is extremely lively. The researchers confirmed that BMP signaling makes neuroblastoma cells rather more susceptible to retinoic acid.
“Unexpectedly, we found that cells expressing genes from the BMP signaling pathway were very sensitive to retinoic acid,” stated co-first and co-corresponding creator Min Pan, Ph.D., St. Jude Division 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 growth to drive metastatic neuroblastoma cell demise
Utilizing gene modifying expertise, the scientists uncovered the connection between BMP signaling and retinoic acid. They assembled a bunch of neuroblastoma cell traces vulnerable to retinoic acid, then lower out genes to search out which have been liable for the drug’s exercise. Genes within the BMP pathway had the biggest impact whereas offering a believable rationalization for retinoic acid’s various outcomes in sufferers.
“We found that, in neuroblastoma, BMP signaling works with retinoic acid signaling in the same way as during development,” stated co-first creator Yinwen Zhang, Ph.D., St. Jude Division of Computational Biology. Zhang characterised how transcription components, the proteins that bind DNA to control gene expression, led to completely different ends in extremely 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,” Zhang stated.
“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 stated. “Now, we can look for similar processes in other diseases to design less toxic and more effective treatment strategies.”
Extra info:
Min Pan et al, Bone morphogenetic protein (BMP) signaling determines neuroblastoma cell destiny and sensitivity to retinoic acid, Nature Communications (2025). DOI: 10.1038/s41467-025-57185-y
Supplied by
St. Jude Youngsters’s Analysis Hospital
Quotation:
Scientists remedy thriller of how the drug retinoic acid works to deal with neuroblastoma (2025, February 28)
retrieved 28 February 2025
from https://medicalxpress.com/information/2025-02-scientists-mystery-drug-retinoic-acid.html
This doc is topic to copyright. Aside from any honest dealing for the aim of personal examine or analysis, no
half could also be reproduced with out the written permission. The content material is offered for info functions solely.
