The tumour microenvironment plays an important role in tumour proliferation, invasion, and metastasis. In particular, cancer cells can exist in heterogeneous states within the complex tumour microenvironment including different nutrient accessibility, oxygen concentration, extracellular pH, and extracellular matrix (ECM) stiffness. Cancer cell characteristics vary among individual cells and metabolic reprogramming is a key feature of tumour microenvironmental adaptation. Cancer cells can switch nutrient source depending on the micro-environment with variation in the effect of aerobic glycolysis. Although heterogeneous metabolism in cancer cells is expected, experimental approaches to analyse cell metabolism at single cell resolution are limited.
In order to investigate heterogeneous cancer cell metabolism, I validated a fluorescence resonance energy transfer (FRET)-based glucose biosensor in breast cancer cell lines. Notably, I observed breast cancer cell lines have heterogeneous intracellular glucose levels and I analysed the functional significance of this metabolic heterogeneity. Multiplexed imaging clarified that high glucose cells take in and consume glucose faster than low glucose cells. Metabolomic analysis further revealed that high and low glucose cells mainly employ glycolysis and oxidative phosphorylation (OXPHOS), respectively. This inter-cellular heterogeneity is established by phosphoinositide 3-kinase (PI3K) signalling pathway and actin cytoskeletal dynamics. Migrating cells dramatically increase intracellular glucose levels by activating the PI3K/AKT signalling pathway and actin cytoskeletal remodelling. PI3K inhibitors can supress glycolysis and the proliferation of breast cancer cells. However, a subset of cells have a PI3K-independent mechanism to regulate glycolysis. Histone acetylation and its reader Bromodomain regulate cell metabolism. Combinatorial inhibition of PI3K and Bromodomain can effectively supress tumour growth.