ZFIN ID: ZDB-PUB-200731-18
Ganglioneuromas are driven by activated AKT and can be therapeutically targeted with mTOR inhibitors
Tao, T., Shi, H., Wang, M., Perez-Atayde, A.R., London, W.B., Gutierrez, A., Lemos, B., Durbin, A.D., Look, A.T.
Date: 2020
Source: The Journal of experimental medicine   217(10): (Journal)
Registered Authors: Durbin, Adam, Gutierrez, Alejandro, Look, A. Thomas, Shi, Hui
Keywords: none
Microarrays: GEO:GSE135682
MeSH Terms:
  • Animals
  • Animals, Genetically Modified
  • Antineoplastic Agents/pharmacology*
  • Apoptosis
  • Cell Cycle
  • Ganglioneuroma/drug therapy
  • Ganglioneuroma/metabolism*
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Neuroblastoma/drug therapy
  • Neuroblastoma/metabolism
  • Proto-Oncogene Proteins c-akt/metabolism*
  • Signal Transduction
  • TOR Serine-Threonine Kinases/antagonists & inhibitors*
  • TOR Serine-Threonine Kinases/metabolism
  • Zebrafish
PubMed: 32728700 Full text @ J. Exp. Med.
Peripheral sympathetic nervous system tumors are the most common extracranial solid tumors of childhood and include neuroblastoma, ganglioneuroblastoma, and ganglioneuroma. Surgery is the only effective therapy for ganglioneuroma, which may be challenging due to the location of the tumor and involvement of surrounding structures. Thus, there is a need for well-tolerated presurgical therapies that could reduce the size and extent of ganglioneuroma and therefore limit surgical morbidity. Here, we found that an AKT-mTOR-S6 pathway was active in human ganglioneuroma but not neuroblastoma samples. Zebrafish transgenic for constitutively activated myr-Akt2 in the sympathetic nervous system were found to develop ganglioneuroma without progression to neuroblastoma. Inhibition of the downstream AKT target, mTOR, in zebrafish with ganglioneuroma effectively reduced the tumor burden. Our results implicate activated AKT as a tumorigenic driver in ganglioneuroma. We propose a clinical trial of mTOR inhibitors as a means to shrink large ganglioneuromas before resection in order to reduce surgical morbidity.