Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism
- Rice University, United States
- University of Texas MD Anderson Cancer Center, United States
- University of Texas, MD Anderson, United States
- Baylor College of Medicine, United States
- Departments of Pathology and Translational Molecular Pathology, Ahmad Center for Pancreatic Cancer Research, United States
- Stanford University, 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.
Article and author information
Author details
Reviewing Editor
- Chi Van Dang, University of Pennsylvania, United States
Version history
- Received: July 21, 2015
- Accepted: February 26, 2016
- Accepted Manuscript published: February 27, 2016 (version 1)
- Version of Record published: April 13, 2016 (version 2)
Copyright
© 2016, Zhao et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism
eLife 5:e10250.
https://doi.org/10.7554/eLife.10250
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