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

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.