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.

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.

Metrics

  • 19,368
    views
  • 6,276
    downloads
  • 721
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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

Share this article

https://doi.org/10.7554/eLife.10250

Further reading

    1. Cell Biology
    John H Day, Catherine M Della Santina ... Laurie A Boyer
    Tools and Resources

    Expansion microscopy (ExM) enables nanoscale imaging using a standard confocal microscope through the physical, isotropic expansion of fixed immunolabeled specimens. ExM is widely employed to image proteins, nucleic acids, and lipid membranes in single cells; however, current methods limit the number of samples that can be processed simultaneously. We developed High-throughput Expansion Microscopy (HiExM), a robust platform that enables expansion microscopy of cells cultured in a standard 96-well plate. Our method enables ~4.2 x expansion of cells within individual wells, across multiple wells, and between plates. We also demonstrate that HiExM can be combined with high-throughput confocal imaging platforms to greatly improve the ease and scalability of image acquisition. As an example, we analyzed the effects of doxorubicin, a known cardiotoxic agent, on human cardiomyocytes (CMs) as measured by the Hoechst signal across the nucleus. We show a dose-dependent effect on nuclear DNA that is not observed in unexpanded CMs, suggesting that HiExM improves the detection of cellular phenotypes in response to drug treatment. Our method broadens the application of ExM as a tool for scalable super-resolution imaging in biological research applications.

    1. Cell Biology
    2. Developmental Biology
    Sofía Suárez Freire, Sebastián Perez-Pandolfo ... Mariana Melani
    Research Article

    Eukaryotic cells depend on exocytosis to direct intracellularly synthesized material toward the extracellular space or the plasma membrane, so exocytosis constitutes a basic function for cellular homeostasis and communication between cells. The secretory pathway includes biogenesis of secretory granules (SGs), their maturation and fusion with the plasma membrane (exocytosis), resulting in release of SG content to the extracellular space. The larval salivary gland of Drosophila melanogaster is an excellent model for studying exocytosis. This gland synthesizes mucins that are packaged in SGs that sprout from the trans-Golgi network and then undergo a maturation process that involves homotypic fusion, condensation, and acidification. Finally, mature SGs are directed to the apical domain of the plasma membrane with which they fuse, releasing their content into the gland lumen. The exocyst is a hetero-octameric complex that participates in tethering of vesicles to the plasma membrane during constitutive exocytosis. By precise temperature-dependent gradual activation of the Gal4-UAS expression system, we have induced different levels of silencing of exocyst complex subunits, and identified three temporarily distinctive steps of the regulated exocytic pathway where the exocyst is critically required: SG biogenesis, SG maturation, and SG exocytosis. Our results shed light on previously unidentified functions of the exocyst along the exocytic pathway. We propose that the exocyst acts as a general tethering factor in various steps of this cellular process.