GSE135682
Aberrant AKT Activation Drives Ganglioneuroma and Can Be Therapeutically Targeted by mTOR Inhibitors
Peripheral sympathetic nervous system tumors are the most common extra-cranial pediatric tumors in children and include neuroblastoma, ganglioneuroma and intermixed ganglioneuroblastoma. Ganglioneuroma can be induced by activating mutations of the RET proto-oncogene or activated Ras in murine models, but the etiology and molecular pathogenesis of this disease is unknown for the majority of human ganglioneuromas. Surgery is the only effective therapy for ganglioneuroma which can be challenging due to tumor location and compression of surrounding structures. Thus, there is great potential benefit to the definition of presurgical therapies that can reduce the size and extent of these tumors, and therefore limit morbidity. We found high levels of phosphorylated AKT in most of human ganglioneuromas, but only in a small portion of human poorly differentiated neuroblastomas (p<0.0001, Fisher's exact test). As a result, we created zebrafish transgenic for constitutively activated myr-Akt2 in the sympathetic nervous system. These zebrafish were found to develop benign ganglioneuroma without progression to neuroblastoma. Zebrafish tumors displayed high expression of phosphorylated Akt and the downstream Akt targets, phosphorylated mTOR, S6 and EIF4EBP1. Histopathological and comparative genomic analyses revealed that zebrafish ganglioneuroma highly resembles human ganglioneuroma. Inhibition of the downstream AKT target, mTOR, using clinically available inhibitors effectively reduced tumor burden in zebrafish embryos transplanted with primary ganglioneuroma. Our results implicate activated and phosphorylated AKT as a tumorigenic driver in ganglioneuroma, and propose inhibition of the AKT-target kinase mTOR as an ideal candidate to treat patients with ganglioneuroma. Overall design: RNA-Seq for zebrafish tumor cells from MYCN and myrAKT transgenic fish