Architectural control of metabolic plasticity in epithelial cancer cells

Metabolic plasticity enables cancer cells to switch between glycolysis and oxidative phosphorylation to adapt to changing conditions during cancer progression, whereas metabolic dependencies limit plasticity. To understand a role for the architectural environment in these processes we examined metabolic dependencies of cancer cells cultured in flat (2D) and organotypic (3D) environments. Here we show that cancer cells in flat cultures exist in a high energy state (oxidative phosphorylation), are glycolytic, and depend on glucose and glutamine for growth. In contrast, cells in organotypic culture exhibit lower energy and glycolysis, with extensive metabolic plasticity to maintain growth during glucose or amino acid deprivation. Expression of KRAS(G12V) in organotypic cells drives glucose dependence, however cells retain metabolic plasticity to glutamine deprivation. Finally, our data reveal that mechanical properties control metabolic plasticity, which correlates with canonical Wnt signaling. In summary, our work highlights that the architectural and mechanical properties influence cells to permit or restrict metabolic plasticity.

Automated summary

The study found that cancer cells cultured in flat environments primarily rely on oxidative phosphorylation for high energy production and depend on glucose and glutamine for growth, while cells in organotypic culture show lower energy levels and metabolic plasticity to maintain growth during glucose or amino acid deprivation. The mechanical properties were identified to control metabolic plasticity, correlating with canonical Wnt signaling.