Tumor Microenvironment Derived Exosomes Pleiotropically Modulate Cancer Cell Metabolism
Doctor of Philosophy
Exosomes are extracellular vesicles responsible for efficient cell-to-cell communications. We intended to investigate the role of tumor microenvironment (TME) derived exosomes in regulating cancer cell metabolism. We found that the isolated exosomes from cancer-associated fibroblasts (CAFs), a major cellular type in TME were uptaken by cancer cells efficiently. Viability assays proved that CAF-derived exosomes (CDEs) enhanced cancer cells viability in nutrient deprived medium to a large extent. In the followed metabolic tests, we found that CDEs downregulate mitochondrial function in both prostate and pancreatic cancer cells, which causes compensatory upregulation of glycolysis in these cells. We found that the possible mechanism of this metabolic regulation is through transfer of miRNAs by CDEs into the cancer cells. We showed that miRNAs contained in CDEs induced mitochondrial dysfunction. Considering that cancer cells in vivo reside in a nutrient-deprived microenvironment of nutrients deprivation and cancer cells’ avid growth needs huge amounts of nutrients, we proposed that CDEs were able to supply nutrients such as lipids, TCA cycle metabolites and amino acids to cancer cells. To prove this, we cultured cancer cells in nutrients deprived medium which is deprived of glutamine, pyruvate, lysine, phenylalanine, and leucine. CDEs were added to the medium to prove that CDEs can maintain cancer cells growth in nutrient deprived conditions similar to complete medium. Surprisingly, the CDEs added to the nutrient-deprived medium endowed cancer cells ability to maintain growth similar to complete medium. The direct rationale to explain it is that CDEs transferred nutrients to and were being utilized by cancer cells. The high throughput metabolomics methods showed that CDEs contained lipids, TCA cycle metabolites, and amino acids. Our results convincingly demonstrate that not only do exosomes enhance the phenomenon of “Warburg effect” in tumors, but remarkably, contain de novo “off-the-shelf” metabolites within their cargo that can contribute to the entire compendia of central carbon metabolism within cancer cells. Disruption of this CDEs-induced metabolic adaptation in cancer cells might provide a novel therapeutic avenue for exploitation.
Exosomes; Tumor microenvironment; Cancer cell metabolism