Medulloblastomas comprise a molecularly diverse set of malignant pediatric brain tumors in which patients are stratified according to different prognostic risk groups that span from very good to very poor. Metastasis at diagnosis is most often a marker of poor prognosis and the relapse incidence is higher in these children. Medulloblastoma relapse is almost always fatal and recurring cells have, apart from resistance to standard of care, acquired genetic and epigenetic changes that correlate with an increased dormancy state, cell state reprogramming and immune escape. Here, we review means to carefully study metastasis and relapse in preclinical models, in light of recently described molecular subgroups. We will exemplify how therapy resistance develops at the cellular level, in a specific niche or from therapy-induced secondary mutations. We further describe underlying molecular mechanisms on how tumors acquire the ability to promote leptomeningeal dissemination and discuss how they can establish therapy-resistant cell clones. Finally, we describe some of the ongoing clinical trials of high-risk medulloblastoma and suggest or discuss more individualized treatments that could be of benefit to specific subgroups.
髓母细胞瘤是一组分子多样性的恶性儿童脑肿瘤，患者根据不同的预后风险组进行分层，其预后范围从极好到极差。诊断时出现转移通常是预后不良的标志，且这些儿童的复发率更高。髓母细胞瘤复发几乎总是致命的，复发的细胞除了对标准治疗产生耐药性外，还获得了与休眠状态增强、细胞状态重编程和免疫逃逸相关的遗传和表观遗传改变。本文结合近期描述的分子亚型，综述了在临床前模型中深入研究转移和复发的方法。我们将举例说明在细胞水平、特定微环境中或由治疗诱导的继发性突变如何导致耐药性的产生。我们进一步描述了肿瘤获得促进软脑膜播散能力的潜在分子机制，并探讨了它们如何建立耐药细胞克隆。最后，我们介绍了一些正在进行的高风险髓母细胞瘤临床试验，并提出或讨论了可能对特定亚组有益的更个体化治疗方案。
Drivers Underlying Metastasis and Relapse in Medulloblastoma and Targeting Strategies
肿瘤(癌症)患者之家