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

  • 19,346
    views
  • 6,272
    downloads
  • 714
    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
    2. Plant Biology
    Masanori Izumi, Sakuya Nakamura ... Shinya Hagihara
    Research Article

    Plants distribute many nutrients to chloroplasts during leaf development and maturation. When leaves senesce or experience sugar starvation, the autophagy machinery degrades chloroplast proteins to facilitate efficient nutrient reuse. Here, we report on the intracellular dynamics of an autophagy pathway responsible for piecemeal degradation of chloroplast components. Through live-cell monitoring of chloroplast morphology, we observed the formation of chloroplast budding structures in sugar-starved leaves. These buds were then released and incorporated into the vacuolar lumen as an autophagic cargo termed a Rubisco-containing body. The budding structures did not accumulate in mutants of core autophagy machinery, suggesting that autophagosome creation is required for forming chloroplast buds. Simultaneous tracking of chloroplast morphology and autophagosome development revealed that the isolation membranes of autophagosomes interact closely with part of the chloroplast surface before forming chloroplast buds. Chloroplasts then protrude at the site associated with the isolation membranes, which divide synchronously with autophagosome maturation. This autophagy-related division does not require DYNAMIN-RELATED PROTEIN 5B, which constitutes the division ring for chloroplast proliferation in growing leaves. An unidentified division machinery may thus fragment chloroplasts for degradation in coordination with the development of the chloroplast-associated isolation membrane.

    1. Cell Biology
    Weihong Xiong, Maozhen Qin, Haining Zhong
    Short Report

    Protein kinase A (PKA) plays essential roles in diverse cellular functions. However, the spatiotemporal dynamics of endogenous PKA upon activation remain debated. The classical model predicts that PKA catalytic subunits dissociate from regulatory subunits in the presence of cAMP, whereas a second model proposes that catalytic subunits remain associated with regulatory subunits following physiological activation. Here, we report that different PKA subtypes, as defined by the regulatory subunit, exhibit distinct subcellular localization at rest in CA1 neurons of cultured hippocampal slices. Nevertheless, when all tested PKA subtypes are activated by norepinephrine, presumably via the β-adrenergic receptor, catalytic subunits translocate to dendritic spines but regulatory subunits remain unmoved. These differential spatial dynamics between the subunits indicate that at least a significant fraction of PKA dissociates. Furthermore, PKA-dependent regulation of synaptic plasticity and transmission can be supported only by wildtype, dissociable PKA, but not by inseparable PKA. These results indicate that endogenous PKA regulatory and catalytic subunits dissociate to achieve PKA function in neurons.