Medulloblastoma (MB) is a childhood malignant brain tumour comprising four main subgroups characterized by different genetic alterations and rate of mortality. Among MB subgroups, patients with enhanced levels of the c-MYC oncogene (MB_Group3) have the poorest prognosis. Here we identify a previously unrecognized role of the pro-autophagy factor AMBRA1 in regulating MB. We demonstrate that AMBRA1 expression depends on c-MYC levels and correlates with Group 3 patient poor prognosis; also, knockdown of AMBRA1 reduces MB stem potential, growth and migration of MB_Group3 stem cells. At a molecular level, AMBRA1 mediates these effects by suppressing SOCS3, an inhibitor of STAT3 activation. Importantly, pharmacological inhibition of autophagy profoundly affects both stem and invasion potential of MB_Group3 stem cells, and a combined anti-autophagy and anti-STAT3 approach impacts the MB_Group3 outcome. Taken together, our data support the c-MYC/AMBRA1/STAT3 axis as a strong oncogenic signalling pathway with significance for both patient stratification strategies and targeted treatments of MB_Group3.

髓母细胞瘤 (MB) 是一种儿童期恶性脑肿瘤，包括四个主要亚组，其特征在于不同的遗传改变和死亡率。在 MB 亚组中，c-MYC 致癌基因（MB _Group3）水平升高的患者预后最差。在这里，我们确定了前自噬因子 AMBRA1 在调节 MB 中的先前未被认识的作用。我们证明 AMBRA1 表达依赖于 c-MYC 水平并与第 3 组患者预后不良相关；此外，AMBRA1 的敲低降低了 MB 茎的潜力、MB _{Group3的生长和迁移}干细胞。在分子水平上，AMBRA1 通过抑制 STAT3 激活抑制剂 SOCS3 来介导这些作用。重要的是，自噬的药理抑制作用深刻影响 MB _Group3干细胞的干细胞和侵袭潜力，而联合抗自噬和抗 STAT3 方法会影响 MB _Group3的结果。总之，我们的数据支持 c-MYC/AMBRA1/STAT3 轴作为强致癌信号通路，对患者分层策略和 MB _Group3的靶向治疗具有重要意义。