Brain-Mimetic 3D Culture Platforms Allow Investigation of Cooperative Effects of Extracellular Matrix Features on Therapeutic Resistance in Glioblastoma.
Brain-Mimetic 3D Culture Platforms Allow Investigation of Cooperative Effects of Extracellular Matrix Features on Therapeutic Resistance in Glioblastoma.
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拟脑 3D 培养平台可以研究细胞外基质特征对胶质母细胞瘤治疗耐药性的协同影响。
DOI：
10.1158/0008-5472.can-17-2429
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发表时间：
2018
期刊：
影响因子：
11.2
通讯作者：
Seidlits,StephanieK
中科院分区：
文献类型：
--
作者：
Xiao,Weikun;Zhang,Rongyu;Sohrabi,Alireza;Ehsanipour,Arshia;Sun,Songping;Liang,Jesse;Walthers,ChristopherM;Ta,Lisa;Nathanson,DavidA;Seidlits,StephanieK
胶质母细胞瘤（GBM）肿瘤表现出潜在的可操作的基因改变，靶向治疗在治疗其他癌症中有效。然而，这些疗法在GBM患者中大多失败。一个值得注意的例子是EGFR激酶抑制剂，尽管在50%的GBM中EGFR过表达和/或突变，但其临床疗效较差。在解决这一问题时，临床前模型可能受到无法准确复制GBM细胞与脑细胞外基质（ECM）的独特方面的病理生理相互作用的限制，ECM相对富含透明质酸（HA）和柔韧性。在这项研究中，我们提出了一个模拟大脑的生物材料ECM平台，用于3D培养患者来源的GBM细胞，并以改进的病理生理特性作为实验模型。与原位异种移植物实验相比，我们开发的新型生物材料培养比胶质球培养更好地保留了对EGFR抑制获得性抗性的生理和动力学。为了达到这一结果，需要对生物材料支架的HA含量和力学性能进行正交调节。总的来说，我们的研究结果表明，GBM细胞受体和支架成分之间的特异性相互作用如何显著有助于抵抗EGFR抑制的细胞毒性作用。意义：胶质母细胞瘤的三维培养支架比目前的患者来源的细胞培养和异种移植模型提供了更好的生理表征。癌症Res;78 (5);1358 - 70。AACR©2017。
Glioblastoma (GBM) tumors exhibit potentially actionable genetic alterations against which targeted therapies have been effective in treatment of other cancers. However, these therapies have largely failed in GBM patients. A notable example is kinase inhibitors of EGFR, which display poor clinical efficacy despite overexpression and/or mutation of EGFR in >50% of GBM. In addressing this issue, preclinical models may be limited by the inability to accurately replicate pathophysiologic interactions of GBM cells with unique aspects of the brain extracellular matrix (ECM), which is relatively enriched in hyaluronic acid (HA) and flexible. In this study, we present a brain-mimetic biomaterial ECM platform for 3D culturing of patient-derived GBM cells, with improved pathophysiologic properties as an experimental model. Compared with orthotopic xenograft assays, the novel biomaterial cultures we developed better preserved the physiology and kinetics of acquired resistance to the EGFR inhibition than gliomasphere cultures. Orthogonal modulation of both HA content and mechanical properties of biomaterial scaffolds was required to achieve this result. Overall, our findings show how specific interactions between GBM cell receptors and scaffold components contribute significantly to resistance to the cytotoxic effects of EGFR inhibition.Significance:Three-dimensional culture scaffolds of glioblastoma provide a better physiological representation over current methods of patient-derived cell culture and xenograft models.Cancer Res; 78(5); 1358–70. ©2017 AACR.