AbstractThe aerobic glycolysis is a hallmark of cancer glucose metabolism. Several studies have suggested that cancer-derived extracellular vesicles (EVs) can modulate glucose metabolism in adjacent cells and promote disease progression. Here we suggest that EVs originated from cancer cell with highly glycolytic activity can modulate glucose metabolism in the recipient cancer cells with relative low glycolytic activity, and further induce cell proliferation. Two types of breast cancer cell lines with different levels of glycolytic activity, MDA-MB-231 of a claudin low-type breast cancer cell and MCF7 of luminal type breast cancer cell, were selected and co-cultured using indirect co-culture system such as transwell system or microfluidic system. Glucose uptake of the recipient MCF7 cells was markedly increased after co-culture with MDA-MB-231 cells. MCF7 cells after co-culture with MDA-MB-231-tdTomato cells represented multiple tdTomato signal inside the cell, which proved that EVs originated from MDA-MB-231-tdTomato were transferred to MCF7 cell. In addition, serine phosphorylation of PKM2 necessary for tumorigenesis was highly activated, and tyrosine phosphorylation of PKM2 suggesting activated aerobic glycolysis was also increased in the co-cultured MCF7 cells. Proteomic profiling of the co-cultured MCF7 cells revealed the proliferation and dedifferentiation of MCF7 cells, and further confirmed epithelial-mesenchymal transition (EMT), which is a key phenomenon for cancer metastasis. In the transcriptomic analysis, glycolysis increased in co-cultured MCF7 cells, and the component analysis of genes associated with glycolysis revealed that the next major component after cytoplasm was extracellular exosome. Proteomic analysis of EVs revealed that there were important proteins in the EV such as EGFR, ERBB2 and MAPK for phosphorylating PKM2. This phenomenon suggests the potential for aggressive cancer cells to affect other cancer cells through EV mediators.
EGF receptor stimulation shifts breast cancer cell glucose metabolism toward glycolytic flux through PI3 kinase signaling