Institute of Human Genetics, University Hospital Düsseldorf, Heinrich-Heine-Universität, Universitätsstr. 1, 40225 Düsseldorf, Germany.
Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome 00161, Italy.
Cell Rep. 2021 Sep 7;36(10):109656. doi: 10.1016/j.celrep.2021.109656.
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-α) 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.
多形性胶质母细胞瘤（GBM）具有促进自我更新、肿瘤增殖和复发的神经胶质瘤干细胞（GSCs）。了解 GSCs 自我更新的机制可以提供靶向治疗干预。然而，对 GSCs 基本生物学的了解不足是阻碍这些努力的一个重大瓶颈。在这里，我们表明，患者来源的 GSCs 募集了大量的蛋白质，这些蛋白质确保了暂时纤毛的解体，从而抑制了纤毛发生。耗尽纤毛解体复合物的成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上来诱导一部分 GSCs 的纤毛发生。重要的是，恢复纤毛发生使 GSCs 能够从自我更新切换到分化。最后，通过基于类器官的脑胶质瘤侵袭测定和在小鼠中的脑异种移植，我们确定纤毛发生诱导的分化可以防止 GSCs 浸润大脑。我们的研究结果说明了纤毛作为决定 GSCs 命运的分子开关的作用，并表明诱导纤毛发生是一种有吸引力的策略，可以干预 GSCs 的增殖。
