Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism

Hongyun Zhao, Lifeng Yang, Joelle Baddour, Abhinav Achreja, Vincent Bernard, Tyler Moss, Juan C. Marini, Thavisha Tudawe, Elena G. Seviour, F. Anthony San Lucas, Hector Alvarez, Sonal Gupta, Sourindra N. Maiti, Laurence Cooper, Donna Peehl, Prahlad T. Ram, Anirban Maitra, Deepak Nagrath

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article numbere10250
JournaleLife
Volume5
Issue numberFEBRUARY2016
DOIs
StatePublished - Feb 27 2016
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Medicine(all)
  • Neuroscience(all)

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