Glioblastoma (GBM) is a highly infiltrative brain cancer, which is thus difficult to operate. GBM cells frequently harbor Epidermal Growth Factor Receptor amplification (EGFRwt) and/or activating mutation (EGFRvIII), generating at least two different cellular subpopulations within the tumor. We examined the relationship between the diffusive architectures of GBM tumors and the paracrine interactions between those subpopulations. Our aim was to shed light on what drives GBM cells to reach large cell-cell distances, and whether this characteristic can be manipulated. We established a methodology that quantifies the infiltration abilities of cancer cells through computation of cell-cell separation distance distributions in 3D. We found that aggressive EGFRvIII cells modulate the migration and infiltrative properties of EGFRwt cells. EGFRvIII cells secrete HGF and IL6, leading to enhanced activity of Src protein in EGFRwt cells, and rendering EGFRwt cells higher velocity and augmented ability to spread. Src inhibitor, dasatinib, at low non-toxic concentrations, reduced the infiltrative properties of EGFRvIII/EGFRwt neurospheres. Furthermore, dasatinib treatment induced compact multicellular microstructure packing of EGFRvIII/EGFRwt cells, impairing their ability to spread. Prevention of cellular infiltration or induction of compact microstructures may assist the detection of GBM tumors and tumor remnants in the brains and improve their surgical removal.

中文翻译：

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解剖胶质母细胞瘤亚群之间的串扰在肿瘤细胞扩散中的作用。

胶质母细胞瘤（GBM）是高度浸润性脑癌，因此难以手术。GBM细胞经常带有表皮生长因子受体扩增（EGFRwt）和/或活化突变（EGFRvIII），在肿瘤内产生至少两个不同的细胞亚群。我们研究了GBM肿瘤的扩散结构与这些亚群之间旁分泌相互作用之间的关系。我们的目的是阐明驱动GBM细胞达到较大的细胞间距离的原因，以及是否可以操纵此特征。我们建立了一种通过计算3D细胞-细胞分离距离分布来量化癌细胞浸润能力的方法。我们发现侵袭性EGFRvIII细胞调节EGFRwt细胞的迁移和浸润特性。EGFRvIII细胞分泌HGF和IL6，导致EGFRwt细胞中Src蛋白的活性增强，并使EGFRwt细胞具有更高的速度和增强的扩散能力。低无毒浓度的Src抑制剂dasatinib降低了EGFRvIII / EGFRwt神经球的浸润特性。此外，达沙替尼治疗可诱导EGFRvIII / EGFRwt细胞紧凑的多细胞微观结构堆积，从而损害其扩散能力。防止细胞浸润或诱导致密的微结构可能有助于检测GBM肿瘤和大脑中的肿瘤残留物，并改善其手术切除率。降低了EGFRvIII / EGFRwt神经球的浸润特性。此外，达沙替尼治疗可诱导EGFRvIII / EGFRwt细胞紧凑的多细胞微观结构堆积，从而损害其扩散能力。防止细胞浸润或诱导致密的微结构可能有助于检测GBM肿瘤和大脑中的肿瘤残留物，并改善其手术切除率。降低了EGFRvIII / EGFRwt神经球的浸润特性。此外，达沙替尼治疗可诱导EGFRvIII / EGFRwt细胞紧凑的多细胞微观结构堆积，从而损害其扩散能力。防止细胞浸润或诱导致密的微结构可能有助于检测GBM肿瘤和大脑中的肿瘤残留物，并改善其手术切除率。