It has become evident
that physical stimuli of the cellular microenvironment
transmit mechanical cues regulating key cellular functions, such as
proliferation, migration, and malignant transformation. Accumulating
evidence suggests that tumor cells face variable mechanical stimuli
that may induce metabolic rewiring of tumor cells. However, the knowledge
of how tumor cells adapt metabolism to external mechanical cues is
still limited. We therefore designed soft 3D collagen scaffolds mimicking
a pathological mechanical environment to decipher how liver tumor
cells would adapt their metabolic activity to physical stimuli of
the cellular microenvironment. Here, we report that the soft 3D microenvironment
upregulates the glycolysis of HepG2 and Alexander cells. Both cell
lines adapt their mitochondrial activity and function under growth
in the soft 3D microenvironment. Cells grown in the soft 3D microenvironment
exhibit marked mitochondrial depolarization, downregulation of mitochondrially
encoded cytochromecoxidase I, and slow proliferation
rate in comparison with stiff monolayer cultures. Our data reveal
the coupling of liver tumor glycolysis to mechanical cues. It is proposed
here that soft 3D collagen scaffolds can serve as a useful model for
future studies of mechanically regulated cellular functions of various
liver (potentially other tissues as well) tumor cells.