Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
Department of Environmental Health & Molecular and Integrative Physiological Sciences Program, Harvard T.H. Chan School of Public Health, Boston, MA.
J Exp Med. 2020 Oct 5;217(10). doi: 10.1084/jem.20191871.
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.
外周交感神经系统肿瘤是儿童最常见的颅外实体瘤，包括神经母细胞瘤、神经节母细胞瘤和神经节细胞瘤。手术是神经节细胞瘤唯一有效的治疗方法，但由于肿瘤的位置和周围结构的受累，手术可能具有挑战性。因此，需要耐受良好的术前治疗方法，以缩小神经节细胞瘤的大小和范围，从而限制手术的发病率。在这里，我们发现 AKT-mTOR-S6 通路在人神经节细胞瘤中活跃，但在神经母细胞瘤样本中不活跃。在交感神经系统中表达组成型激活的 myr-Akt2 的斑马鱼被发现会发展为神经节细胞瘤，但不会进展为神经母细胞瘤。用神经节细胞瘤的斑马鱼抑制下游 AKT 靶点 mTOR，可有效减少肿瘤负担。我们的研究结果表明，激活的 AKT 是神经节细胞瘤的致癌驱动因素。我们建议进行一项 mTOR 抑制剂的临床试验，作为在切除前缩小大型神经节细胞瘤的手段，以降低手术发病率。
