Journal
ACTA BIOMATERIALIA
Volume 27, Issue -, Pages 13-20Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.actbio.2015.08.041
Keywords
Micropillar array; Epithelial-to-mesenchymal transition (EMT); Focal adhesion; Drug screening
Funding
- Creative Allied Program through the Korea Research Council of Fundamental Science and Technology - Ministry of Science, ICT and Future Planning [CAP-12-1]
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Here, we demonstrate the possible applications of micropillar arrays in screening anti-metastasis drugs. Human lung adenocarcinoma A549 cells incubated in multiwell plates containing micropillars exhibited markedly different physical/biochemical behavior depending on pillar dimensions. In particular, A549 cells grown in plates containing 2-mu m diameter, 16-mu m pitched pillar arrays showed epithelial-to-mesenchymal transition (EMT)-like behavior; cell body elongation, and highly increased activation of the focal adhesion kinase (FAK)-Src-paxillin signaling cascade. FAK is the most prominent kinase involved in dynamic regulation of the actin cytoskeleton and cell adhesion, migration, and invasion. Activation of FAK, a hallmark of cancer cell adhesion and migration, is normally induced by various growth factors, such as transforming growth factor-beta (TGF-beta). Here, we found that pillar-mediated activation of signaling molecules mimicked that induced by TGF-beta. Notably, micropillar arrays with specific dimensions accelerated the elongation of cells, an effect linked to the activation of signaling molecules related to EMT. Micropillar-induced FAK activation could be arrested by the casein kinase-2 (CK2) inhibitor CX-4945, a drug candidate with activity against TGF-beta-induced cancer cell metastasis, demonstrating the possibility of using inorganic microstructures for cell-based drug screening. Statement of Significance In this work, we have fabricated flexible substrates with regular arrays of micrometersized pillars, and used them to grow A549 human lung adenocarcinoma cells. Cells exhibit dramatically different behavior depending on the intervals of pillars. Especially, cells grown in certain pillar structures show epithelial-to mesenchmal transition (EMT)-like morphology and related molecules, which is similar to the activation obtained using expensive cytokine TGF-beta. Based on the fact that pillar arrays may activate EMT like transition, screening of anti-cancer drug using pillar arrays have demonstrated as well in our work. Our study confirms that mechanical stimulation may exert similar effects with chemical stimulation, and such mechanical structures could be used as a large-scale drug screening platforms. Cell morphogenesis on engineered substrate is not new, but the present work could be distinguished with its unique fabrication process that can mass produce the structures and it could be applied for high-throughput drug screening. Also, we suggest the formation of focal adhesions on pillar structures and consequent strain as the possible mechanism behind the observed EMT-like transition. Currently, we are working on full-scale profiling of metabolomics and proteomics of cells grown in large-scale pillar arrays as well. (C) 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.
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