Aldaregia Juncal, Errarte Peio, Olazagoitia-Garmendia Ane, Gimeno Marian, Uriz Jose Javier, Gershon Timothy R, Garcia Idoia, Matheu Ander
Cellular Oncology group, Biodonostia Health Research Institute, Dr. Beguiristain s/n, 20014 San Sebastian, Spain.
Donostia University Hospital, 20014 San Sebastian, Spain.
Cancers (Basel). 2020 Apr 17;12(4):997. doi: 10.3390/cancers12040997.
Medulloblastoma is the most common and malignant pediatric brain tumor in childhood. It originates from dysregulation of cerebellar development, due to an excessive proliferation of cerebellar granule neuron precursor cells (CGNPs). The underlying molecular mechanisms, except for the role of SHH and WNT pathways, remain largely unknown. ERBB4 is a tyrosine kinase receptor whose activity in cancer is tissue dependent. In this study, we characterized the role of ERBB4 during cerebellum development and medulloblastoma progression paying particular interests to its role in CGNPs and medulloblastoma stem cells (MBSCs). Our results show that ERBB4 is expressed in the CGNPs during cerebellum development where it plays a critical role in migration, apoptosis and differentiation. Similarly, it is enriched in the population of MBSCs, where also controls those critical processes, as well as self-renewal and tumor initiation for medulloblastoma progression. These results are translated to clinical samples where high levels of ERBB4 correlate with poor outcome in Group 4 and all medulloblastomas groups. Transcriptomic analysis identified critical processes and pathways altered in cells with knock-down of . These results highlight the impact and underlying mechanisms of ERBB4 in critical processes during cerebellum development and medulloblastoma.
髓母细胞瘤是儿童期最常见且恶性的小儿脑肿瘤。它起源于小脑发育失调，这是由于小脑颗粒神经元前体细胞（CGNP）过度增殖所致。除了SHH和WNT信号通路的作用外，其潜在的分子机制在很大程度上仍不清楚。ERBB4是一种酪氨酸激酶受体，其在癌症中的活性取决于组织类型。在本研究中，我们阐述了ERBB4在小脑发育和髓母细胞瘤进展过程中的作用，特别关注其在CGNP和髓母细胞瘤干细胞（MBSC）中的作用。我们的结果表明，ERBB4在小脑发育过程中的CGNP中表达，在细胞迁移、凋亡和分化中发挥关键作用。同样，它在MBSC群体中富集，在那里它也控制这些关键过程以及髓母细胞瘤进展中的自我更新和肿瘤起始。这些结果在临床样本中得到验证，其中ERBB4的高表达与4组及所有髓母细胞瘤组的不良预后相关。转录组分析确定了敲低ERBB4的细胞中改变的关键过程和信号通路。这些结果突出了ERBB4在小脑发育和髓母细胞瘤关键过程中的影响及潜在机制。
