Abstract
Extracellular matrix (ECM) mechanical properties upregulate cancer invasion, cell contractility, and focal adhesion formation. Alteration in energy metabolism is a known characteristic of cancer cells (i.e., Warburg effect) and modulates cell invasion. There is little evidence to show if collagen density can alter cancer cell metabolism. We investigated changes in energy metabolism due to collagen density in five breast cell lines by measuring the fluorescence lifetime of NADH. We found that only triple-negative breast cancer cells, MDA-MB231 and MDA-MB468 cells, had an increased population of bound NADH, indicating an oxidative phosphorylation (OXPHOS) signature, as collagen density decreased. When inhibiting ROCK and cell contractility, MDA-MB231 cells on glass shifted from glycolysis (GLY) to OXPHOS, confirming the intricate relationship between mechanosensing and metabolism. MCF10A cells showed less significant changes in metabolism, shifting towards GLY as collagen density decreased. The MCF-7 and T-47D, less invasive breast cancer cells, compared to the MDA-MB231 and MDA-MB468 cells, showed no changes regardless of substrate. In addition, OXPHOS or GLY inhibitors in MDA-MB231 cells showed dramatic shifts from OXPHOS to GLY or vice versa. These results provide an important link between cellular metabolism, contractility, and collagen density in human breast cancer.
Highlights
Cancer cells can modulate their energy metabolism to meet nutritional, biosynthesis and respiration requirements for maintaining malignancy
Tilghman et al postulated that cellular metabolism can be altered when MDA-MB231 cells are cultured on soft (300 Pa) versus stiff (19200 Pa) matrices due to the fact that cells stayed in the G1 phase cell cycle phase longer[32]
In our lab, we have shown that the mechanical properties of collagen obtained through Second harmonic generation (SHG) and image correlation spectroscopy (ICS) correlated to those obtained by rheology or scanning electron microscopy images[31,33]
Summary
Cancer cells can modulate their energy metabolism to meet nutritional, biosynthesis and respiration requirements for maintaining malignancy. Recent studies have shown that integrin-mediated adhesions interact with the metabolic pathway of the cell through the PI3K/AKT/mTOR pathway and that this could be a potential method of switching the Warburg effect[20,21,22] Many of these studies use biochemical assays which are invasive and often lose information which exists in live cell samples. Inhibition of cell contractility with the addition of Y-27632 shifted all the cells on all substrates to a more OXPHOS signature compared to their uninhibited controls This further shows that integrin-mediated adhesions behave as mechanosensors and these adhesions can alter metabolism. MCF-7 and T-47D, the less invasive breast cancer cells, were tested and did not show changes in metabolic signatures
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