Abstract
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 KRASG12V 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.
Highlights
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
It has become appreciated that cancer cells may display metabolic plasticity and switch between glycolysis and oxidative phosphorylation (OXPHOS) depending on microenvironmental context in different tissues[8,9]
Whereas flat cultures showed a marked dependence on glucose (80% reduction in growth in the absence of glucose) no growth difference was observed for organotypic cells cultured in glucosereplete or glucose-free medium (Fig. 1c–e; Supplementary Fig. S1a)
Summary
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. Cells in organotypic culture exhibit lower energy and glycolysis, with extensive metabolic plasticity to maintain growth during glucose or amino acid deprivation. Epithelial cancer cells and nontransformed cells cultured in flat 2D contexts are dependent on glucose and glutamine for growth, whereas in organotypic 3D cultures they exhibit metabolic plasticity to maintain growth during nutrient deprivation. Underlying these differences are unique metabolic programs between flat and organotypic cultures. We show that metabolic plasticity is in part regulated by extracellular stiffness and Wnt signaling Together this demonstrates that the architectural environment plays a key role in regulating metabolic dependency and adaptability of cancer cells
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