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

Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism.

Author information

1
Laboratory for Systems Biology of Human Diseases, Rice University, Houston, United States.
2
Department of Chemical and Biomolecular Engineering, Rice University, Houston, United States.
3
Departments of Pathology and Translational Molecular Pathology, Ahmad Center for Pancreatic Cancer Research, University of Texas MD Anderson Cancer Center, Houston, United States.
4
Department of Systems Biology, University of Texas, MD Anderson, Houston, United States.
5
Baylor College of Medicine, Houston, United States.
6
Department of Pediatrics, University of Texas MD Anderson Cancer Center, Houston, United States.
7
Department of Urology, School of Medicine, Stanford University, Stanford, United States.
8
Department of Bioengineering, Rice University, Houston, United States.

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

Comment in

PMID:
26920219
PMCID:
PMC4841778
DOI:
10.7554/eLife.10250
[Indexed for MEDLINE]
Free PMC Article

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