Department of Developmental and Stem Cell Biology, Beckman Research Institute of the City of Hope, Duarte, CA, USA.
Division of Comparative Medicine, Beckman Research Institute of the City of Hope, Duarte, CA, USA.
Commun Biol. 2021 May 11;4(1):552. doi: 10.1038/s42003-021-02075-4.
During mammalian brain development, neural progenitor cells proliferate extensively but can ensure the production of correct numbers of various types of mature cells by balancing symmetric proliferative versus asymmetric differentiative cell divisions. This process of cell fate determination may be harnessed for developing cancer therapy. Here, we test this idea by targeting KIF20A, a mitotic kinesin crucial for the control of cell division modes, in a genetic model of medulloblastoma (MB) and human MB cells. Inducible Kif20a knockout in both normal and MB-initiating granule neuron progenitors (GNPs) causes early cell cycle exit and precocious neuronal differentiation without causing cytokinesis failure and suppresses the development of Sonic Hedgehog (SHH)-activated MB. Inducible KIF20A knockdown in human MB cells inhibits proliferation both in cultures and in growing tumors. Our results indicate that targeting the fate specification process of nascent daughter cells presents a novel avenue for developing anti-proliferation treatment for malignant brain tumors.
在哺乳动物大脑发育过程中，神经祖细胞广泛增殖，但通过平衡对称的增殖与不对称的分化细胞分裂，可以确保产生正确数量的各种成熟细胞。细胞命运决定的这个过程可用于开发癌症治疗方法。在这里，我们通过靶向有丝分裂驱动蛋白 KIF20A 来检验这一观点，KIF20A 是一种有丝分裂驱动蛋白，对控制细胞分裂模式至关重要，我们在髓母细胞瘤（MB）和人 MB 细胞的遗传模型中研究了它。在正常和起始颗粒神经元祖细胞（GNPs）中诱导性敲除 Kif20a 会导致早期细胞周期退出和过早的神经元分化，而不会导致胞质分裂失败，并抑制 Sonic Hedgehog（SHH）激活的 MB 的发展。在人 MB 细胞中诱导性敲低 KIF20A 可抑制培养物和生长肿瘤中的增殖。我们的结果表明，针对新形成的子细胞的命运特化过程为开发恶性脑肿瘤的抗增殖治疗提供了新途径。
