title: A spatiotemporally defined in vitro microenvironment for controllable signal delivery and drug screening.
abstract: Cancer metastasis and drug resistance are important malignant tumor phenotypes that cause roughly 90% mortality in human cancers. Current therapeutic strategies, however, face substantial challenges partially due to a lack of applicable pre-clinical models and drug-screening platforms. Notably, microscale and three-dimensional (3D) tissue culture platforms capable of mimicking in vivo microenvironments to replicate physiological conditions have become vital tools in a wide range of cellular and clinical studies. Here, we present a microfluidic device capable of mimicking a configurable tumor microenvironment to study in vivo-like cancer cell migration as well as screening of inhibitors on both parental tumors and migratory cells. In addition, a novel evaporation-based paper pump was demonstrated to achieve adaptable and sustainable concentration gradients for up to 6 days in this model. This straightforward modeling approach allows for fast patterning of a wide variety of cell types in 3D and may be further integrated into biological assays. We also demonstrated cell migration from tumor spheroids induced by an epidermal growth factor (EGF) gradient and exhibited lowered expression of an epithelial marker (EpCAM) compared with parental cells, indicative of partial epithelial-mesenchymal transition (EMT) in this process. Importantly, pseudopodia protrusions from the migratory cells - critical during cancer metastasis - were demonstrated. Insights gained from this work offer new opportunities to achieve active control of in vitro tumor microenvironments on-demand, and may be amenable towards tailored clinical applications.
authors.affiliation: Institute of Applied Mechanics, National Taiwan University, Taipei, Taiwan, Republic of China. andrew@iam.ntu.edu.tw.
authors.forename: Ching-Te
authors.initials: CT
authors.lastname: Kuo
authors.forename: Hao-Kai
authors.initials: HK
authors.lastname: Liu
authors.forename: Guan-Syuan
authors.initials: GS
authors.lastname: Huang
authors.forename: Chi-Hao
authors.initials: CH
authors.lastname: Chang
authors.forename: Chen-Lin
authors.initials: CL
authors.lastname: Chen
authors.forename: Ken-Chao
authors.initials: KC
authors.lastname: Chen
authors.forename: Ruby Yun-Ju
authors.initials: RY
authors.lastname: Huang
authors.forename: Ching-Hung
authors.initials: CH
authors.lastname: Lin
authors.forename: Hsinyu
authors.initials: H
authors.lastname: Lee
authors.forename: Chiun-Sheng
authors.initials: CS
authors.lastname: Huang
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Wo
mesh_terms: D000951:Antigens, Neoplasm / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D004815:Epidermal Growth Factor / Q000494:pharmacology; D000071858:Epithelial Cell Adhesion Molecule; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D006801:Humans; D061986:MCF-7 Cells; D046210:Microfluidic Analytical Techniques / Q000295:instrumentation / Q000379:methods; D008954:Models, Biological; D017239:Paclitaxel / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D018874:Spheroids, Cellular / Q000166:cytology / Q000187:drug effects; D059016:Tumor Microenvironment
chemical_list: D000951:Antigens, Neoplasm; D015815:Cell Adhesion Molecules; D000071858:Epithelial Cell Adhesion Molecule; D012333:RNA, Messenger; D004815:Epidermal Growth Factor; D017239:Paclitaxel