Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism

By Hongyun Zhao, Lifeng Yang, Joelle A Baddour, Abhinav Achreja, V. Bernard, T. Moss, J. Marini, Thavisha Tudawe, E. Seviour, F. S. San Lucas and 8 more. eLife, 2016

792 citations recorded by the source corpus.

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. DOI: http://dx.doi.org/10.7554/eLife.10250.001

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/64d343d0a9dabf89df6c2d683e688d49d56fc9ef

How researchers see this paper

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In Cancer Research

1. G. Brooks
2. S. Venneti
3. Yan Luo
4. Ben Wang
5. Lifeng Yang
6. Deepak Nagrath
7. M. Qasim
8. Muniyandi Jeyaraj

In Molecular Biology

1. G. Brooks
2. S. Venneti
3. Larry Norton
4. Yan Luo
5. Ben Wang
6. Lifeng Yang
7. Deepak Nagrath
8. M. Qasim

Citations in the corpus

• Review of the Isolation, Characterization, Biological Function, and Multifarious Therapeutic Approaches of Exosomes (2019, background): “Cancer-Associated Fibroblasts (CAFs) derived exosomes are also capable of supporting tumor growth by providing nutrients to malignant cells [244].”
• Metabolic Interactions in the Tumor Microenvironment (2017, background): “Prostate and pancreatic CAF-derived exosomes have also been shown to contain nutrient cargo (including a spectrum of amino acids, fatty acids and TCA cycle metabolites) that are taken in and utilized by cancer cells [94, 95] (Fig.”
• Packaging and transfer of mitochondrial DNA via exosomes regulate escape from dormancy in hormonal therapy-resistant breast cancer (2017, positive): “Thus, we propose that EVs play a pivotal role in cancer metabolism, with potentially broad implications for their control (27).”
• Exosome-Based Cell-Cell Communication in the Tumor Microenvironment (2018, background): “…Switch miRNA- 302d, −29b, −22, −155, −25, −29a, −23a, −21, −16, −222, −24, −199a, −125b, −144 Down-regulation of genes related to OXPHOS by CAF exosomes Zhao et al., 2016 Lactate, Acetate, Citrate, Pyruvate, α-Ketoglutarate, Fumarate, Malate, aminoacids such as Gln, Arg, Glu, Pro, Ala,…”
• Exosomes: key players in cancer and potential therapeutic strategy (2020, background): “cancer cells by inhibiting mitochondrial oxidative phosphorylation, thereby increasing glycolysis and glutamine dependent reduction carboxylation in cancer cells.(71) In breast cancer patients, the expression levels of miR-21, miR-378e, and miR-143 in CDEs were higher than those in NFs.”
• Exosome Theranostics: Biology and Translational Medicine (2018, background): “Most importantly, normal cell-derived exosomes have low immunogenicity and are well tolerated [114].”
• Glutaminolysis: A Hallmark of Cancer Metabolism. (2017, background): “Exosomes, which are vesicles secreted by cells, can act as metabolite cargo to support prostate cancer growth under low-nutrient conditions via a KRAS-independent mechanism (Figure 8c) (136).”