Abstract:
UNLABELLED: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-μm diameter, 16-μm 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-β (TGF-β). Here, we found that pillar-mediated activation of signaling molecules mimicked that induced by TGF-β. 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-β-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-β. 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.
journal_name
Acta Biomaterjournal_title
Acta biomaterialiaauthors
Kim J,Choi WJ,Moon SH,Jung J,Park JK,Kim SH,Lee JOdoi
10.1016/j.actbio.2015.08.041subject
Has Abstractpub_date
2015-11-01 00:00:00pages
13-20eissn
1742-7061issn
1878-7568pii
S1742-7061(15)30085-4journal_volume
27pub_type
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journal_title:Acta biomaterialia
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journal_title:Acta biomaterialia
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journal_title:Acta biomaterialia
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pub_type: 杂志文章,评审
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journal_title:Acta biomaterialia
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doi:10.1016/j.actbio.2011.01.010
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journal_title:Acta biomaterialia
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doi:10.1016/j.actbio.2019.01.051
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