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Microfluidic Tumor-on-a-Chip Model to Study Tumor Metabolic Vulnerability

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...

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Autores principales: Ayuso, Jose M, Rehman, Shujah, Farooqui, Mehtab, Virumbrales-Muñoz, María, Setaluri, Vijayasaradhi, Skala, Melissa C, Beebe, David J
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7730115/
https://www.ncbi.nlm.nih.gov/pubmed/33260673
http://dx.doi.org/10.3390/ijms21239075
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author Ayuso, Jose M
Rehman, Shujah
Farooqui, Mehtab
Virumbrales-Muñoz, María
Setaluri, Vijayasaradhi
Skala, Melissa C
Beebe, David J
author_facet Ayuso, Jose M
Rehman, Shujah
Farooqui, Mehtab
Virumbrales-Muñoz, María
Setaluri, Vijayasaradhi
Skala, Melissa C
Beebe, David J
author_sort Ayuso, Jose M
collection PubMed
description 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.
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spelling pubmed-77301152020-12-12 Microfluidic Tumor-on-a-Chip Model to Study Tumor Metabolic Vulnerability Ayuso, Jose M Rehman, Shujah Farooqui, Mehtab Virumbrales-Muñoz, María Setaluri, Vijayasaradhi Skala, Melissa C Beebe, David J Int J Mol Sci Article 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. MDPI 2020-11-28 /pmc/articles/PMC7730115/ /pubmed/33260673 http://dx.doi.org/10.3390/ijms21239075 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Ayuso, Jose M
Rehman, Shujah
Farooqui, Mehtab
Virumbrales-Muñoz, María
Setaluri, Vijayasaradhi
Skala, Melissa C
Beebe, David J
Microfluidic Tumor-on-a-Chip Model to Study Tumor Metabolic Vulnerability
title Microfluidic Tumor-on-a-Chip Model to Study Tumor Metabolic Vulnerability
title_full Microfluidic Tumor-on-a-Chip Model to Study Tumor Metabolic Vulnerability
title_fullStr Microfluidic Tumor-on-a-Chip Model to Study Tumor Metabolic Vulnerability
title_full_unstemmed Microfluidic Tumor-on-a-Chip Model to Study Tumor Metabolic Vulnerability
title_short Microfluidic Tumor-on-a-Chip Model to Study Tumor Metabolic Vulnerability
title_sort microfluidic tumor-on-a-chip model to study tumor metabolic vulnerability
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7730115/
https://www.ncbi.nlm.nih.gov/pubmed/33260673
http://dx.doi.org/10.3390/ijms21239075
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