Magnetically Integrated Tumor–Vascular Interface System to Mimic Pro-angiogenic Endothelial Dysregulations for On-Chip Drug Testing

肿瘤微环境 粘合连接 内皮干细胞 血管生成 细胞生物学 材料科学 血管内皮生长因子 血管内皮生长因子A 内皮 癌症研究 生物 细胞 体外 钙粘蛋白 生物化学 肿瘤细胞 血管内皮生长因子受体 内分泌学
作者
Vikram Surendran,Simrit Safarulla,Christian M Griffith,Reem Sami Ali,Ankit Madan,William J. Polacheck,Arvind Chandrasekaran
出处
期刊:ACS Applied Materials & Interfaces [American Chemical Society]
卷期号:16 (36): 47075-47088 被引量:1
标识
DOI:10.1021/acsami.4c01766
摘要

The tumor–vascular interface is a critical component of the tumor microenvironment that regulates all of the dynamic interactions between a growing tumor and the endothelial lining of the surrounding vasculature. In this paper, we report the design and development of a custom-engineered tumor–vascular interface system for investigating the early stage tumor-mediated pro-angiogenic dysfunctional behavior of the endothelium. Using representative endothelial cells and triple negative breast cancer cell lines, we established a biomimetic interface between a three-dimensional tumor tissue across a mature, functional endothelial barrier using a magnetically hybrid-integrated tumor–vascular interface system, wherein vasculature-like features containing a monolayer of endothelial cell culture on porous microfluidic channel surfaces were magnetically attached to tumor spheroids generated on a composite polymer-hydrogel microwell plate and embedded in a collagen matrix. Tumor-mediated endothelial microdynamics were characterized by their hallmark behavior such as loss of endothelial adherens junctions, increased cell density, proliferation, and changes in cell spreading and corroborated with endothelial YAP/TAZ nuclear translocation. We further confirm the feasibility of drug-mediated reversal of this pro-angiogenic endothelial organization through two different signaling mechanisms, namely, inhibition of the vascular endothelial growth factor pathway and the Notch signaling pathway, thereby demonstrating the utility of the tumor–vascular interface platform for rapid, early stage prediction of antiangiogenic drug efficacy. Overall, our work emphasizes the importance of our strategic engineering approach for identifying some unique, physiologically relevant aspects of the tumor–vascular interface, which are otherwise difficult to implement using standard in vitro approaches.

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