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Microfluidic Tumor-on-a-Chip Model to Study Tumor Metabolic Vulnerability
Authors:Jose M Ayuso  Shujah Rehman  Mehtab Farooqui  María Virumbrales-Muoz  Vijayasaradhi Setaluri  Melissa C Skala  David J Beebe
Affiliation:1.Department of Pathology & Laboratory Medicine, University of Wisconsin, Madison, WI 53706, USA; (M.F.); (M.V.-M.);2.Morgridge Institute for Research, 330 N Orchard Street, Madison, WI 53715, USA; (S.R.); (M.C.S.);3.Department of Biomedical Engineering, University of Wisconsin, Madison, WI 53706, USA;4.The University of Wisconsin Carbone Cancer Center, University of Wisconsin, Madison, WI 53706, USA;5.Department of Dermatology, University of Wisconsin-Madison, Madison, WI 53706, USA;
Abstract:Tumor-specific metabolic adaptations offer an interesting therapeutic opportunity to selectively destroy cancer cells. However, solid tumors also present gradients of nutrients and waste products across the tumor mass, forcing tumor cells to adapt their metabolism depending on nutrient availability in the surrounding microenvironment. Thus, solid tumors display a heterogenous metabolic phenotype across the tumor mass, which complicates the design of effective therapies that target all the tumor populations present. In this work, we used a microfluidic device to study tumor metabolic vulnerability to several metabolic inhibitors. The microdevice included a central chamber to culture tumor cells in a three-dimensional (3D) matrix, and a lumen in one of the chamber flanks. This design created an asymmetric nutrient distribution across the central chamber, generating gradients of cell viability. The results revealed that tumor cells located in a nutrient-enriched environment showed low to no sensitivity to metabolic inhibitors targeting glycolysis, fatty acid oxidation, or oxidative phosphorylation. Conversely, when cell density inside of the model was increased, compromising nutrient supply, the addition of these metabolic inhibitors disrupted cellular redox balance and led to tumor cell death.
Keywords:tumor metabolism  tumor-on-a-chip  microfluidics  redox ratio
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