Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism

Elife. 2016 Feb 27;5:e10250. doi: 10.7554/eLife.10250.

Abstract

Cancer-associated fibroblasts (CAFs) are a major cellular component of tumor microenvironment in most solid cancers. Altered cellular metabolism is a hallmark of cancer, and much of the published literature has focused on neoplastic cell-autonomous processes for these adaptations. We demonstrate that exosomes secreted by patient-derived CAFs can strikingly reprogram the metabolic machinery following their uptake by cancer cells. We find that CAF-derived exosomes (CDEs) inhibit mitochondrial oxidative phosphorylation, thereby increasing glycolysis and glutamine-dependent reductive carboxylation in cancer cells. Through 13C-labeled isotope labeling experiments we elucidate that exosomes supply amino acids to nutrient-deprived cancer cells in a mechanism similar to macropinocytosis, albeit without the previously described dependence on oncogenic-Kras signaling. Using intra-exosomal metabolomics, we provide compelling evidence that CDEs contain intact metabolites, including amino acids, lipids, and TCA-cycle intermediates that are avidly utilized by cancer cells for central carbon metabolism and promoting tumor growth under nutrient deprivation or nutrient stressed conditions.

Keywords: cancer metabolism; cell biology; exosomes; human; human biology; macropinocytosis; medicine; metabolic flux analysis; reductive carboxylation; tumor microenvironment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Exosomes* / metabolism
  • Fermentation
  • Fibroblasts / metabolism*
  • Glucose / metabolism*
  • Glycolysis
  • Lactic Acid / metabolism
  • Neoplasms / physiopathology*
  • Oxidative Phosphorylation
  • Tumor Microenvironment*

Substances

  • Lactic Acid
  • Glucose