Schaller Research Group at the University of Heidelberg, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, 69120, Heidelberg, Germany.
Molecular Mechanisms of Tumor Invasion (V077), DKFZ, Im Neuenheimer Feld 581, 69120, Heidelberg, Germany.
Acta Neuropathol. 2019 Aug;138(2):275-293. doi: 10.1007/s00401-019-02021-z. Epub 2019 May 6.
Glioblastomas strongly invade the brain by infiltrating into the white matter along myelinated nerve fiber tracts even though the myelin protein Nogo-A prevents cell migration by activating inhibitory RhoA signaling. The mechanisms behind this long-known phenomenon remained elusive so far, precluding a targeted therapeutic intervention. This study demonstrates that the prevalent activation of AKT in gliomas increases the ER protein-folding capacity and enables tumor cells to utilize a side effect of RhoA activation: the perturbation of the IRE1α-mediated decay of SPARC mRNA. Once translation is initiated, glioblastoma cells rapidly secrete SPARC to block Nogo-A from inhibiting migration via RhoA. By advanced ultramicroscopy for studying single-cell invasion in whole, undissected mouse brains, we show that gliomas require SPARC for invading into white matter structures. SPARC depletion reduces tumor dissemination that significantly prolongs survival and improves response to cytostatic therapy. Our finding of a novel RhoA-IRE1 axis provides a druggable target for interfering with SPARC production and underscores its therapeutic value.
胶质母细胞瘤通过沿着有髓神经纤维束浸润白质强烈侵袭大脑，尽管髓鞘蛋白 Nogo-A 通过激活抑制性 RhoA 信号来阻止细胞迁移。到目前为止，这一众所周知的现象背后的机制仍难以捉摸，从而阻止了靶向治疗干预。本研究表明，在神经胶质瘤中普遍存在的 AKT 激活增加了 ER 蛋白折叠能力，并使肿瘤细胞能够利用 RhoA 激活的一种副作用：干扰 SPARC mRNA 通过 IRE1α 介导的衰减。一旦翻译被启动，神经胶质瘤细胞就会迅速分泌 SPARC，阻止 Nogo-A 通过 RhoA 抑制迁移。通过用于研究整个未解剖的小鼠大脑中单细胞侵袭的先进超微技术，我们表明神经胶质瘤需要 SPARC 才能侵入白质结构。SPARC 耗竭减少肿瘤播散，显著延长生存并改善对细胞抑制治疗的反应。我们发现的一种新的 RhoA-IRE1 轴为干扰 SPARC 产生提供了一个可药物治疗的靶点，并强调了其治疗价值。
