Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism

  1. Hongyun Zhao
  2. Lifeng Yang
  3. Joelle Baddour
  4. Abhinav Achreja
  5. Vincent Bernard
  6. Tyler Moss
  7. Juan Marini
  8. Thavisha Tudawe
  9. Elena G Seviour
  10. F Anthony San Lucas
  11. Hector Alvarez
  12. Sonal Gupta
  13. Sourindra N Maiti
  14. Laurence Cooper
  15. Donna Peehl
  16. Prahlad T Ram
  17. Anirban Maitra
  18. Deepak Nagrath  Is a corresponding author
  1. Rice University, United States
  2. University of Texas MD Anderson Cancer Center, United States
  3. University of Texas, MD Anderson, United States
  4. Baylor College of Medicine, United States
  5. Departments of Pathology and Translational Molecular Pathology, Ahmad Center for Pancreatic Cancer Research, United States
  6. 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

  1. Hongyun Zhao

    Laboratory for Systems Biology of Human Diseases, Rice University, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Lifeng Yang

    Laboratory for Systems Biology of Human Diseases, Rice University, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Joelle Baddour

    Laboratory for Systems Biology of Human Diseases, Rice University, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Abhinav Achreja

    Laboratory for Systems Biology of Human Diseases, Rice University, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Vincent Bernard

    Departments of Pathology and Translational Molecular Pathology, Ahmad Center for Pancreatic Cancer Research, University of Texas MD Anderson Cancer Center, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Tyler Moss

    Department of Systems Biology, University of Texas, MD Anderson, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Juan Marini

    Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Thavisha Tudawe

    Department of Chemical and Biomolecular engineering, Rice University, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Elena G Seviour

    Department of Systems Biology, University of Texas, MD Anderson, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. F Anthony San Lucas

    Departments of Pathology and Translational Molecular Pathology, Ahmad Center for Pancreatic Cancer Research, University of Texas MD Anderson Cancer Center, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Hector Alvarez

    Departments of Pathology and Translational Molecular Pathology, Departments of Pathology and Translational Molecular Pathology, Ahmad Center for Pancreatic Cancer Research, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Sonal Gupta

    Departments of Pathology and Translational Molecular Pathology, Ahmad Center for Pancreatic Cancer Research, University of Texas MD Anderson Cancer Center, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Sourindra N Maiti

    Department of Pediatrics, University of Texas MD Anderson Cancer Center, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Laurence Cooper

    Department of Pediatrics, University of Texas MD Anderson Cancer Center, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Donna Peehl

    Department of Urology, School of Medicine, Stanford University, Stanford, United States
    Competing interests
    The authors declare that no competing interests exist.
  16. Prahlad T Ram

    Department of Systems Biology, University of Texas, MD Anderson, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  17. Anirban Maitra

    Departments of Pathology and Translational Molecular Pathology, Ahmad Center for Pancreatic Cancer Research, University of Texas MD Anderson Cancer Center, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  18. Deepak Nagrath

    Laboratory for Systems Biology of Human Diseases, Rice University, Houston, United States
    For correspondence
    dn7@rice.edu
    Competing interests
    The authors declare that no competing interests exist.

Reviewing Editor

  1. Chi Van Dang, University of Pennsylvania, United States

Publication history

  1. Received: July 21, 2015
  2. Accepted: February 26, 2016
  3. Accepted Manuscript published: February 27, 2016 (version 1)
  4. 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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  1. Hongyun Zhao
  2. Lifeng Yang
  3. Joelle Baddour
  4. Abhinav Achreja
  5. Vincent Bernard
  6. Tyler Moss
  7. Juan Marini
  8. Thavisha Tudawe
  9. Elena G Seviour
  10. F Anthony San Lucas
  11. Hector Alvarez
  12. Sonal Gupta
  13. Sourindra N Maiti
  14. Laurence Cooper
  15. Donna Peehl
  16. Prahlad T Ram
  17. Anirban Maitra
  18. Deepak Nagrath
(2016)
Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism
eLife 5:e10250.
https://doi.org/10.7554/eLife.10250
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