Lamellipodin-RICTOR Signaling Mediates Glioblastoma Cell Invasion and Radiosensitivity Downstream of EGFR.
Lamellipodin-RICTOR Signaling Mediates Glioblastoma Cell Invasion and Radiosensitivity Downstream of EGFR.
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DOI：
10.3390/cancers13215337
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发表时间：
2021-10-24
期刊：
影响因子：
5.2
通讯作者：
Vehlow A
中科院分区：
文献类型：
--
作者：
Moritz S;Krause M;Schlatter J;Cordes N;Vehlow A
胶质母细胞瘤患者预后差，生存期有限，只有几个月。这种肿瘤的不可治愈性主要是由于胶质母细胞瘤细胞的侵袭性以及治疗抗性。更好地了解分子过程驱动积极的渗透和抵抗治疗干预将使新的治疗方法的发展。在这项研究中，我们确定了一个迄今未描述的作用，细胞骨架蛋白Lamelliopodin胶质母细胞瘤细胞。我们确定Lamellipodin基本上介导胶质母细胞瘤的侵袭、增殖和放射敏感性。我们的结果进一步确定了一个新的Lamelliodin-RICTOR-EGFR信号轴，使胶质母细胞瘤放射生存。胶质母细胞瘤是一种需求未得到满足的肿瘤类型，尽管开发了多模式治疗策略。导致胶质母细胞瘤患者预后不良的主要因素是导致胶质母细胞瘤持续存在和复发的多种遗传和表观遗传变化。通过细胞表面受体介导的细胞外信号补充这些因子，其进一步有助于促进促侵袭和促存活信号传导，从而导致胶质母细胞瘤治疗抗性。赋予这种治疗抗性的潜在机制知之甚少。在这里，我们表明，细胞骨架调节Lamellipodin（LPD）介导的胶质母细胞瘤细胞的侵袭性，增殖和放射敏感性。磷酸化蛋白质组分析确定了表皮生长因子受体（EGFR）信号轴通常在胶质母细胞瘤中过度活跃，依赖于LPD。从机制上讲，EGFR信号传导与Lpd和哺乳动物雷帕霉素靶蛋白（RICTOR）的雷帕霉素不敏感伴侣之间的相互作用共同调节胶质母细胞瘤的放射敏感性。总的来说，我们的研究结果证明了LPD在胶质母细胞瘤细胞的辐射反应和侵袭性中的重要功能。因此，我们发现了一种新的Lpd驱动的耐药机制，它为复杂的胶质母细胞瘤耐药网络增加了一个额外的关键方面。
Glioblastoma patients suffer from a poor prognosis with a limited survival of just a few months. Incurability of this tumor mainly results from glioblastoma cell invasiveness as well as therapy resistance. A better understanding of the molecular processes driving aggressive infiltration and resistance to therapeutic intervention would enable the development of new therapeutic approaches. In this study, we identify a so-far-undescribed role of the cytoskeleton protein Lamellipodin in glioblastoma cells. We determined that Lamellipodin essentially mediates glioblastoma invasion, proliferation and radiosensitivity. Our results further identify a new Lamellipodin-RICTOR-EGFR signaling axis enabling glioblastoma radiation survival. Glioblastoma is a tumor type of unmet need despite the development of multimodal treatment strategies. The main factors contributing to the poor prognosis of glioblastoma patients are diverse genetic and epigenetic changes driving glioblastoma persistence and recurrence. Complemented are these factors by extracellular cues mediated through cell surface receptors, which further aid in fostering pro-invasion and pro-survival signaling contributing to glioblastoma therapy resistance. The underlying mechanisms conferring this therapy resistance are poorly understood. Here, we show that the cytoskeleton regulator Lamellipodin (Lpd) mediates invasiveness, proliferation and radiosensitivity of glioblastoma cells. Phosphoproteome analysis identified the epidermal growth factor receptor (EGFR) signaling axis commonly hyperactive in glioblastoma to depend on Lpd. Mechanistically, EGFR signaling together with an interaction between Lpd and the Rapamycin-insensitive companion of mammalian target of rapamycin (RICTOR) jointly regulate glioblastoma radiosensitivity. Collectively, our findings demonstrate an essential function of Lpd in the radiation response and invasiveness of glioblastoma cells. Thus, we uncover a novel Lpd-driven resistance mechanism, which adds an additional critical facet to the complex glioblastoma resistance network.
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