title: Modeling of cancer metastasis and drug resistance via biomimetic nano-cilia and microfluidics.
abstract: Three-dimensional (3D) tissue culture platforms that are capable of mimicking in vivo microenvironments to replicate physiological conditions are vital tools in a wide range of cellular and clinical studies. Here, learning from the nature of cilia in lungs - clearing mucus and pathogens from the airway - we develop a 3D culture approach via flexible and kinetic copolymer-based chains (nano-cilia) for diminishing cell-to-substrate adhesion. Multicellular spheroids or colonies were tested for 3-7 days in a microenvironment consisting of generated cells with properties of putative cancer stem cells (CSCs). The dynamic and reversible regulation of epithelial-mesenchymal transition (EMT) was examined in spheroids passaged and cultured in copolymer-coated dishes. The expression of CSC markers, including CD44, CD133, and ABCG2, and hypoxia signature, HIF-1α, was significantly upregulated compared to that without the nano-cilia. In addition, these spheroids exhibited chemotherapeutic resistance in vitro and acquired enhanced metastatic propensity, as verified from microfluidic chemotaxis assay designed to replicate in vivo-like metastasis. The biomimetic nano-cilia approach and microfluidic device may offer new opportunities to establish a rapid and cost-effective platform for the study of anti-cancer therapeutics and CSCs.
authors.affiliation: Institute of Applied Mechanics, National Taiwan University, Taipei, Taiwan, ROC.
authors.forename: Ching-Te
authors.initials: CT
authors.lastname: Kuo
authors.affiliation: School of Biomedical Science, Ohio State University, Columbus, USA.
authors.forename: Chi-Ling
authors.initials: CL
authors.lastname: Chiang
authors.affiliation: Department of Life Science, National Taiwan University, Taipei, Taiwan, ROC.
authors.forename: Chi-Hao
authors.initials: CH
authors.lastname: Chang
authors.affiliation: Institute of Applied Mechanics, National Taiwan University, Taipei, Taiwan, ROC.
authors.forename: Hao-Kai
authors.initials: HK
authors.lastname: Liu
authors.affiliation: Institute of Applied Mechanics, National Taiwan University, Taipei, Taiwan, ROC.
authors.forename: Guan-Syuan
authors.initials: GS
authors.lastname: Huang
authors.affiliation: Department of Obstetrics & Gynaecology, National University Hospital, Singapore; Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors.forename: Ruby Yun-Ju
authors.initials: RY
authors.lastname: Huang
authors.affiliation: Department of Life Science, National Taiwan University, Taipei, Taiwan, ROC. Electronic address: hsinyu@ntu.edu.tw.
authors.forename: Hsinyu
authors.initials: H
authors.lastname: Lee
authors.affiliation: Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan, ROC. Electronic address: huangcs@ntu.edu.tw.
authors.forename: Chiun-Sheng
authors.initials: CS
authors.lastname: Huang
authors.affiliation: Institute of Applied Mechanics, National Taiwan University, Taipei, Taiwan, ROC. Electronic address: andrew@iam.ntu.edu.tw.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Wo
mesh_terms: D032701:Biomimetics; D045744:Cell Line, Tumor; D002923:Cilia / Q000502:physiology*; D019008:Drug Resistance, Neoplasm; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D044085:Microfluidics; D008954:Models, Biological; D049329:Nanostructures; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology
keywords: Biomimetic; CSC; Drug resistance; EMT; Metastasis; Microfluidics