Cilium induction triggers differentiation of glioma stem cells
Cilium induction triggers differentiation of glioma stem cells
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DOI：
10.1016/j.celrep.2021.109656
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发表时间：
2021-09-07
期刊：
影响因子：
8.8
通讯作者：
Gopalakrishnan, Jay
中科院分区：
文献类型：
--
作者：
Goranci-Buzhala, Gladiola;Mariappan, Aruljothi;Gopalakrishnan, Jay
多形性胶质母细胞瘤（GBM）具有促进自我更新、肿瘤增殖和复发的胶质瘤干细胞（GSC）。了解GSC自我更新的机制可以提供有针对性的治疗干预。然而，对GSC基础生物学的了解不足是阻碍这些努力的一个重要瓶颈。在这里，我们表明，患者来源的GSC招募蛋白质水平升高，确保颞纤毛拆卸，导致抑制纤毛发生。消耗纤毛拆卸复合物组分足以通过将血小板衍生生长因子受体-α（PDGFR-α）重新定位到新诱导的纤毛来诱导GSC亚组中的纤毛发生。重要的是，恢复纤毛发生使GSC能够从自我更新转变为分化。最后，使用基于类器官的胶质瘤侵袭试验和小鼠脑异种移植物，我们确定纤毛发生诱导的分化可以防止GSC浸润到大脑中。我们的研究结果说明了纤毛作为决定GSC命运的分子开关的作用，并建议纤毛诱导作为干预GSC增殖的有吸引力的策略。
Glioblastoma multiforme (GBM) possesses glioma stem cells (GSCs) that promote self-renewal, tumor propagation, and relapse. Understanding the mechanisms of GSCs self-renewal can offer targeted therapeutic interventions. However, insufficient knowledge of GSCs' fundamental biology is a significant bottleneck hindering these efforts. Here, we show that patient-derived GSCs recruit elevated levels of proteins that ensure the temporal cilium disassembly, leading to suppressed ciliogenesis. Depleting the cilia disassembly complex components is sufficient to induce ciliogenesis in a subset of GSCs via relocating platelet-derived growth factor receptor-alpha (PDGFR-a) to a newly induced cilium. Importantly, restoring ciliogenesis enabled GSCs to switch from self-renewal to differentiation. Finally, using an organoid-based glioma invasion assay and brain xenografts in mice, we establish that ciliogenesis-induced differentiation can prevent the infiltration of GSCs into the brain. Our findings illustrate a role for cilium as a molecular switch in determining GSCs' fate and suggest cilium induction as an attractive strategy to intervene in GSCs proliferation.