Holmberg Karl O, Borgenvik Anna, Zhao Miao, Giraud Géraldine, Swartling Fredrik J
Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, 75185 Uppsala, Sweden.
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
Cancers (Basel). 2024 Apr 30;16(9):1752. doi: 10.3390/cancers16091752.
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特征多样的儿童恶性脑肿瘤，根据预后风险从非常好到非常差的不同分组对患者进行分层。诊断时出现转移通常是预后不良的标志，这些儿童的复发率更高。髓母细胞瘤复发几乎总是致命的，复发细胞除了对标准治疗产生耐药性外，还发生了与休眠状态增加、细胞状态重编程和免疫逃逸相关的遗传和表观遗传变化。在此，我们根据最近描述的分子亚组，综述在临床前模型中仔细研究转移和复发的方法。我们将举例说明治疗耐药性如何在细胞水平、特定微环境中或由治疗诱导的二次突变产生。我们进一步描述肿瘤如何获得促进软脑膜播散能力的潜在分子机制，并讨论它们如何建立治疗耐药细胞克隆。最后，我们描述了一些正在进行的高危髓母细胞瘤临床试验，并提出或讨论可能对特定亚组有益的更个体化治疗方法。
