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Microfluidic Tumor-on-a-Chip Model to Study Tumor Metabolic Vulnerability
Jose M Ayuso1, Shujah Rehman2,3,4, Mehtab Farooqui1
1Department of Pathology & Laboratory Medicine, University of Wisconsin, 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.
Insights
Solid tumors exhibit varied metabolic phenotypes due to nutrient gradients. Targeting tumor cell metabolism with inhibitors proved effective only when nutrient supply was limited, disrupting cellular redox balance and causing cancer cell death.
Area of Science:
- Oncology
- Cancer Metabolism
- Biomedical Engineering
Background:
- Tumor-specific metabolic adaptations are a therapeutic target.
- Solid tumors exhibit nutrient and waste product gradients, leading to heterogeneous metabolic phenotypes.
- This metabolic heterogeneity complicates the development of effective cancer therapies.
Purpose of the Study:
- To investigate tumor metabolic vulnerability to metabolic inhibitors under nutrient-gradients.
- To model the heterogeneous metabolic phenotype of solid tumors.
- To assess the impact of nutrient availability on cancer cell response to metabolic inhibitors.
Main Methods:
- Utilized a microfluidic device with a 3D matrix culture chamber and a lumen.
- Created asymmetric nutrient distribution to generate nutrient gradients across the tumor model.
- Cultured tumor cells and exposed them to metabolic inhibitors targeting glycolysis, fatty acid oxidation, and oxidative phosphorylation.
Main Results:
- Tumor cells in nutrient-rich conditions showed low sensitivity to metabolic inhibitors.
- Increased cell density, leading to compromised nutrient supply, sensitized cells to metabolic inhibitors.
- Metabolic inhibitors disrupted cellular redox balance and induced tumor cell death under nutrient-limited conditions.
Conclusions:
- Tumor metabolic phenotype heterogeneity is driven by microenvironmental nutrient availability.
- Metabolic inhibitors targeting glycolysis, fatty acid oxidation, or oxidative phosphorylation are effective only under nutrient-limited conditions.
- Targeting tumor metabolism requires consideration of nutrient gradients and cell density within solid tumors.
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