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Cited by 927Extracellular vesicles in diseaseCancer, Hypoxia, and MetabolismCancer Cells and Metastasis

Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism

Open access
Zhao, Hongyun, Yang, Lifeng, Baddour, Joelle, Achreja, Abhinav, Bernard, Vincent, Moss, Tyler, Marini, Juan C, Tudawe, Thavisha +10 more·2016·eLife
DOI 10.7554/elife.10250PMC PMC4841778
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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.

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Written from the paper’s full text.

TL;DR

Patient-derived cancer-associated fibroblast exosomes (CDEs) reprogram prostate and pancreatic cancer cell metabolism by inhibiting mitochondrial oxidative phosphorylation and increasing glycolysis and glutamine-dependent reductive carboxylation. CDEs also carry intact metabolite cargo—amino acids, TCA-cycle intermediates, lactate, acetate, and lipids—that can be used by nutrient-deprived cancer cells in a Kras-independent, macropinocytosis-like manner.

Key findings

  • CDEs are internalized by prostate cancer cells; isolated particles were 30–100 nm and expressed CD63. CDEs reduced basal, maximal, and reserve mitochondrial oxygen consumption rate (OCR) and mitochondrial membrane potential, while increasing extracellular acidification rate (ECAR), glucose uptake, and lactate secretion across prostate cancer lines and pancreatic cancer lines.
  • CDEs increased glutamine-dependent reductive carboxylation, shown by increased M5 glutamate, M5 α-ketoglutarate, M5 citrate, M3 fumarate, and M3 malate; they also increased the α-ketoglutarate/citrate ratio and decreased glucose contribution to α-ketoglutarate.
  • Intra-exosomal metabolomics detected lactate, acetate, pyruvate, citrate, α-ketoglutarate, fumarate, malate, multiple amino acids, and intact stearate and palmitate in prostate and pancreatic CDEs. Labeled CDEs contributed approximately 16% of phenylalanine, 14% of glutamine, 12% of lysine, and 5% of leucine pools in PC3 cells under nutrient deprivation.
  • In pancreatic cancer cells, CDEs rescued proliferation under nutrient deprivation in both wild-type Kras BxPC3 and activated Kras MiaPaCa-2 cells, and in doxycycline-inducible Kras-G12D iKras-1 cells, indicating Kras-independent metabolite supply. Acetate contributed 10–15% and pyruvate 3–8% to lipogenesis; CDEs increased acetate contribution and decreased pyruvate contribution to palmitate.

Methods

  • Patient-derived prostate and pancreatic CAFs were used to isolate CDEs; cancer models included prostate lines PC3, DU145, 22RV1, E006AA and pancreatic lines BxPC3, MiaPaCa-2, and iKras-1. Most experiments used 200 μg/ml CDEs, chosen to approximate a physiological CAF-to-cancer-cell ratio of 1–5.
  • Metabolic assays included Seahorse OCR/ECAR, glucose and lactate measurements, mitochondrial membrane potential, microarray and qPCR for OXPHOS genes, NanoString miRNA profiling, and 13C-labeled glucose, glutamine, pyruvate, acetate, leucine, lysine, and phenylalanine tracing with GC-MS and UPLC for intra-exosomal metabolites.
  • Uptake and functional dependence were tested with Cytochalasin D, heparin, chloroquine, and EIPA; statistical comparisons used Student t test with mean ± SD or SEM and p<0.05, p<0.01, or p<0.001 thresholds.

Limitations

  • The paper states that exosome purification can degrade metabolites, so fresh exosomes were used and freeze-thaw avoided; it recommends replenishing exosomes for functional studies. It also notes that the 200 μg/ml working concentration and CAF-to-cancer ratio should be individually estimated for different CAF/cancer systems.
  • The paper states technical limits for miRNA co-transfection: only a small subset of OXPHOS-targeting miRNAs could be tested, OCR reduction was moderate, and further studies are needed to uncover ETC inhibition by CDE-derived miRNAs.
  • The paper states that 72 hr of labeling was insufficient for CAFs to undergo at least one replication, so labeled exosomal metabolites were diluted with unlabeled M0 isoforms; estimated essential amino acid contributions are therefore lower than total contributions over 48 hr, and higher detection would require multiple labeling passages. Evident from the text: the work is largely cell-culture based, with no in vivo tumor-growth experiments reported.

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Integrity signals

Registry

Crossref · 10.7554/elife.10250

Cites

60 of 60 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 69 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    CDEs increase the ratio of α-ketoglutarate to citrate in PC3 cancer cells.

    “we measured the ratio of α-ketoglutarate to citrate abundance in cancer cells and found that exosomes increased this ratio significantly (Figure 4G).”
    Quote in the paperSubstantial claim
  • Findingown data

    CDEs decrease glucose contribution to palmitate in cancer cells.

    “we found that exosomes also decreased glucose contribution to palmitate.”
    Quote in the paperSubstantial claim
  • Findingown data

    Inhibition of electron transport chain by CDEs significantly increased glutamine's reductive carboxylation for biosynthesis in cancer cells.

    “the inhibition of electron transport chain by CDEs significantly increased glutamine’s reductive carboxylation for biosynthesis in cancer cells.”
    Quote in the paperSubstantial claim
  • Findingown data

    CDEs increase lactate levels in cancer cells.

    “We found that the CDEs increased the lactate levels in the cancer cells (Figure 3F, Figure 3—figure supplement 1).”
    Quote in the paperSubstantial claim
  • Findingown data

    Cytochalasin D partially rescues the CDE-induced reduction of OCR in PC3 cells.

    “CytoD could partially rescue this reduction of OCR in PC3 cells, thus confirming the CAF exosomes mediated reduction of OCR in cancer cells (Figure 2D).”
    Quote in the paperSubstantial claim
  • May combine two claims. 43
  • The quote only partly states this claim. 2
  • Classified as probably not a substantial claim. 45

  • May combine two claims.

    Findingown data

    CDEs increase the percentage contribution of glutamine through the reductive pathway and decrease its oxidative contribution to the TCA cycle in cancer cells.

    “This is further substantiated through significant increase in the percentage contribution of glutamine through reductive pathway in the TCA cycle in cancer cells in presence of exosomes when compared to control condition. Also, there was concomitant decrease in the percentage contribution of glutamine through oxidative pathway in the TCA cycle.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Exosomes supply amino acids to nutrient-deprived cancer cells via a macropinocytosis-like mechanism that does not depend on oncogenic Kras signaling, including in wild-type and activated Kras-expressing pancreatic 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.”
    • Also stated in: § Introduction · boosted
      “we demonstrate in wild-type and activated Kras-expressing pancreatic cancer cells that the metabolite cargo delivery mechanism by exosomes is similar to macropinocytosis, albeit without the previously described dependence on oncogenic Kras signaling (Commisso et al., 2013).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Commisso et al., 2013 source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    CDE metabolites are utilized by recipient cancer cells for proliferation, precursor metabolites, and replenishing TCA cycle metabolites.

    “these metabolites are utilized by recipient cancer cells for proliferation, precursor metabolites and replenishing levels of TCA cycle metabolites.”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    Co-transfection of mir-22, let7a, and mir-125b decreases OCR in PC3 cells.

    “we see a decrease in OCR in PC3 cells co-transfected with miRNAs.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    CDEs increase glucose uptake and lactate secretion in prostate cancer cells.

    “CDEs increased glucose uptake and lactate secretion when compared to cancer cells cultured without exogenously added exosomes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    CDEs decrease M0 pyruvate and M0 lactate and increase M1 pyruvate and M1 lactate, suggesting enhanced glycolysis.

    “there was a decrease of M0 pyruvate and M0 lactate with a corresponding increase of M1 pyruvate and M1 lactate, thus suggesting that the exosomes enhance glycolysis.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: M1 pyruvate is only produced by glucose-6-phosphate metabolized by phospho glucoisomerase.

  • May combine two claims.

    Findingown data

    CDEs increase M5 citrate, M3 fumarate, and M3 malate in cancer cells, suggesting increased reliance on reductive glutamine metabolism.

    “there was significant increase in M5 citrate, M3 fumarate and M3 malate in cancer cells in the presence of exogenously added exosomes thus suggesting that cancer cells rely critically on reductive glutamine metabolism when normal mitochondrial function is disrupted by stromal microenvironment (Figure 4D–F).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    CDEs increase M5 glutamate and M5 α-ketoglutarate in cancer cells, indicating enhanced glutamine entry into the TCA cycle.

    “addition of CDEs increased M5 glutamate and M5 α-ketoglutarate in cancer cells thereby indicating that exosomes enhance glutamine’s entry into TCA cycle (Figure 4B,C).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    CDEs increase acetate contribution to lipids and decrease pyruvate contribution to lipids in cancer cells.

    “CDEs increased acetate contribution to lipids (Figure 4N) but decreased the pyruvate contribution (Figure 4O).”
    • Also stated in: § CDEs enhance reductive pathway of glutamine metabolism in cancer cells · plain
      “ISA results confirm these observations, where cancer cells cultured with CDEs showed an increase in acetate’s contribution with a concomitant decrease in pyruvate’s contribution to palmitate production (Figure 4P).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingreasoning

    CDEs reduce the percentage of M2 citrate, M2 α-ketoglutarate, M2 fumarate, M2 malate, and M2 glutamate in cancer cells.

    “the percentage of M2 citrate, M2 α-ketoglutarate, M2 fumarate, M2 malate, and M2 glutamate was also significantly reduced in cancer cells in presence of CDEs (Figure 3I–M).”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    CDEs downregulate transcript levels of OXPHOS-related genes, including ATP synthase complex genes, CYTB, and COXI, in PC3 cells.

    “transcript levels for OXPHOS related ATP synthase complex genes were downregulated in cells cultured with CDEs.”
    • Also stated in: § CDEs downregulate mitochondrial function of prostate cancer cells · plain
      “both cytochrome B (CYTB) and cytochrome C oxidase I (COXI), which are components of Complexes III and IV of the electron transport chain, respectively, have lower transcript expression levels when PC3 cells were cultured with exogenous CDEs (Figure 2H).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    CDEs contain miRNAs that target oxidative phosphorylation genes, and the relative abundance of such miRNAs is higher than most other miRNAs.

    “The relative abundance of miRNAs that target oxidative phosphorylation genes is higher in exosomes than most other miRNA as seen in the density distribution plot (Figure 2I).”
    • Also stated in: § CDEs downregulate mitochondrial function of prostate cancer cells · plain
      “The top 30 most abundant miRNAs across the exosomes sampled, target one or more OXPHOS genes, which is validated by measuring the decrease in mRNA levels of these genes after treatment with exosomes (Figure 2J).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Cancer cells cultured with labeled CDEs show M5 glutamate derived from mitochondrial glutaminolysis and labeled TCA cycle metabolites from labeled 13C-glutamine supplied by CDEs.

    “We also detected M5 glutamate derived from mitochondrial glutaminolysis and labeled TCA cycle metabolites from labeled 13C-glutamine supplied by CDEs (Figure 6B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    CDEs contain high concentrations of citrate and pyruvate and significant presence of α-ketoglutarate, fumarate, and malate.

    “we performed GC-MS analysis for intra-exosomal metabolites and found high concentrations of citrate and pyruvate along with significant presence of α-ketoglutarate, fumarate and malate (Figure 5C).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Exosomes account for approximately 16% of phenylalanine, 14% of glutamine, 12% of lysine, and 5% of leucine pools in PC3 cells.

    “We observed that exosomes account for approximately 16% of phenylalanine, 14% of glutamine, 12% of lysine and 5% of leucine pools in PC3 cells (Figure 6—figure supplement 1A).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    BxPC3 and MiaPaCa-2 show similar extents of metabolic profile regulation and enhanced growth rate due to stromal exosomes.

    “BxPC3 and MiaPaCa-2 showed similar extents of metabolic profile regulation as well as enhanced growth rate because of stromal exosomes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Cancer cells cultured with exosomes have significantly reduced OXPHOS and increased glycolysis.

    “cancer cells cultured with exosomes had significantly reduced OXPHOS with a concomitant increase in glycolysis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    CytoD and heparin inhibit exosome uptake and repress exosome influence on increasing growth rates of BxPC3 and MiaPaCa-2.

    “Through endocytosis inhibitors CytoD and receptor mediated endocytosis inhibitor heparin, we inhibited exosomes uptake, and thereby repressed exosomes' influence on increasing growth rates of pancreatic cancer cells BxPC3 and MiaPaCa-2.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    CDEs reduced mitochondrial oxidative phosphorylation and induced metabolic alterations in cancer cells mimicking hypoxia-induced alterations.

    “In summary, these results suggest that CDEs reduced mitochondrial oxidative phosphorylation and induced metabolic alterations in cancer cells mimicking hypoxia-induced alterations.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Glutamine serves as an anaplerosis substrate to fuel the TCA cycle for energy generation and provides nitrogen for protein synthesis.

    “Glutamine serves as an anaplerosis substrate to fuel the TCA cycle for energy generation and also provides nitrogen for protein synthesis (Dang, 2010; Wise and Thompson, 2010; DeBerardinis and Cheng, 2010; Daye and Wellen, 2012; Gaglio et al., 2009; Johnson et al., 2003; Rajagopalan and DeBerardinis, 2011; Shanware et al., 2011; Weinberg et al., 2010).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Dang, 2010 source

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    • cites Wise and Thompson, 2010

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    • cites DeBerardinis and Cheng, 2010 source

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  • May combine two claims.

    Interpretationown data

    CDEs reprogram cancer cell metabolism through disabling mitochondrial oxidative metabolism and providing de novo 'off the shelf' metabolites through exosomal cargo.

    “Our results demonstrate that patient-derived CDEs reprogram cancer cell metabolism through disabling mitochondrial oxidative metabolism and providing de novo 'off the shelf' metabolites through exosomal cargo.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Cancer-associated fibroblasts (CAFs) are a major cellular component of the tumor microenvironment in most solid cancers.

    “Cancer-associated fibroblasts (CAFs) are a major cellular component of tumor microenvironment in most solid cancers.”
    • Also stated in: § Introduction · plain
      “CAFs are the major constituent of the TME in many cancers (Whiteside, 2008; Allinen et al., 2004; Feig et al., 2012).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Whiteside, 2008 source

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    • cites Allinen et al., 2004 source

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    • cites Feig et al., 2012 source

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  • May combine two claims.

    Interpretationown data

    The metabolic content of exosomes is implicated in CDE-induced increases in cancer cell proliferation, mitochondrial dysfunction, and increased glycolysis.

    “These results implicate metabolic content of exosomes towards observed changes in CDEs-induced increase in cancer cell proliferation, mitochondrial dysfunction and increased glycolysis.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    The miRNAs and their targets identified are based on experimental miRNA abundance data from Nanostring assays followed by miRNA target prediction integrated with AGO-CLIP-SEQ data.

    “The miRNAs and their targets that we have identified are based on experimental miRNA abundance data from Nanostring assays followed by miRNA target prediction integrated with AGO-CLIP-SEQ data (Li et al., 2014).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Li et al., 2014

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  • May combine two claims.

    Interpretationown data

    CDEs decrease the percentage contribution of glucose to α-ketoglutarate and divert it towards lactate in cancer cells.

    “This further confirms that CDEs decreased the percentage contribution of glucose to a-ketoglutarate in cancer cells and instead diverted it towards lactate.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    CDEs induce a Warburg-type phenotype in cancer cells by disabling normal oxidative mitochondrial function with a compensatory increase in glycolysis.

    “The above results conclusively show that CDEs induce a Warburg type phenotype in cancer cells, by disabling normal oxidative mitochondrial function with a compensatory increase in glycolysis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    CAFs downregulate mitochondrial OXPHOS in cancer cells and CDEs play a key role in this reprogramming.

    “These results suggest that CAFs downregulate mitochondrial OXPHOS in cancer cells and CDEs play a key role in this reprogramming.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Exosome-depleted serum was used for cell culture.

    “Exosome-depleted serum was used for cell culture.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Exosomes range between 30-100 nm in diameter, have a bilayered membrane, and express CD63.

    “Exosomes range between 30–100 nm in diameter, have a bilayered membrane (Johnstone et al., 1987) and express surface marker such as CD63 (Christianson et al., 2013).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Johnstone et al., 1987 source

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    • cites Christianson et al., 2013 source

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    Premisecitation

    Exosomes contain proteins, nucleic acids, and miRNAs.

    “Recent studies indicate that they contain proteins, nucleic acids and miRNAs (Ekström et al., 2012; Costa-Silva et al., 2015; Simons and Raposo, 2009).”
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    • cites Simons and Raposo, 2009

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    Premisecitation

    CDEs enhance drug resistance in colorectal cancer stem cells by regulating the Wnt pathway, and this effect can be reversed by inhibiting exosome secretion.

    “Hu et al. have discovered that CDEs enhance drug resistance in colorectal cancer stem cells by regulating the Wnt pathway and this effect can be reversed by inhibiting exosome secretion (Hu et al., 2015).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Hu et al., 2015

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    Premisecitation

    TCA cycle dysfunction leads to oncogenesis by regulating signaling pathways and stabilizing HIF1-α.

    “TCA cycle dysfunction leads to oncogenesis by regulating signaling pathway and stabilizing HIF1-α (Selak et al., 2005).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Selak et al., 2005 source

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    Premisecitation

    Proliferating cells under hypoxia predominantly reductively carboxylate glutamine-generated α-ketoglutarate through IDH 1/2 to generate M5 citrate.

    “Alternatively, proliferating cells under hypoxia have been reported to predominantly reductively carboxylate glutamine generated α-ketoglutarate through IDH 1/2 to generate M5 citrate (Figure 4A) (Metallo, 2012).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Metallo, 2012 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The Warburg effect leads to diversion of glucose to lactate, creating low pH conditions that modulate TME.

    “This leads to diversion of glucose to lactate thereby creating low pH conditions which modulates TME (Warburg et al., 1927; Gatenby et al., 2006; Salimian Rizi et al., 2015).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Warburg et al., 1927 source

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    • cites Salimian Rizi et al., 2015 source

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  • May combine two claims.

    Study design and conductreasoning

    Substrates within CDEs will not be fully 13C labeled because 72 hr are not sufficient for CAFs to undergo at least one replication, so labeled metabolites in CDEs may be diluted with pre-existent unlabeled (M0) isoforms.

    “substrates within CDEs will not be fully 13C labeled since 72 hr are not sufficient for CAFs to undergo at least one replication, and hence labeled metabolites in CDEs may be diluted with pre-existent unlabeled (M0) isoforms.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    CAFs comprise the majority of cell types within the TME, and their reciprocal interactions with cancer cells are well documented.

    “CAFs comprise the majority of cell types within the TME, and their reciprocal interactions with cancer cells have been well documented (Whiteside, 2008; Hazlehurst et al., 2003; Karnoub et al., 2007).”
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    Premisecitation

    CAFs have been shown to regulate cancer cell growth.

    “Since CAFs have been shown to regulate cancer cell growth (Liao et al., 2009)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Liao et al., 2009 source

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    Premisecitation

    The Warburg effect is the reliance of cancer cells on aerobic glycolysis even under normoxia.

    “The Warburg effect, commonly observed characteristic of many cancer types, is identified as the reliance of cancer cells on aerobic glycolysis even under normoxia.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Warburg et al., 1927 source

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    • cites Gatenby et al., 2006 source

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    • cites Salimian Rizi et al., 2015 source

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    Premisecitation

    Macropinocytosis is a mechanism to supply amino acids through extracellular proteins in oncogenic Ras-expressing pancreatic cancer cells.

    “Our results were similar to the process of macropinocytosis, which was revealed as a mechanism to supply amino acids through extracellular proteins in oncogenic Ras-expressing pancreatic cancer cells.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationcitation

    CDEs may not only enhance cancer growth but may also induce chemoresistance.

    “These studies suggest that CDEs may not only enhance cancer growth but may also induce chemoresistance.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Exosomes carry information from one cell to another and reprogram recipient cells.

    “Exosomes carry information from one cell to another and reprogram the recipient cells (Gangoda et al., 2015)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Gangoda et al., 2015 source

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    Premisecitation

    Acetate could be an important source for lipogenic acetyl-CoA in cancer cells, especially under hypoxic conditions.

    “Recently it was shown that acetate could be an important source for lipogenic acetyl-CoA in cancer cells, especially under hypoxic conditions(Kamphorst et al., 2014).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Kamphorst et al., 2014 source

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  • May combine two claims.

    Interpretationown data

    Exosomes can replenish TCA cycle metabolites and act as a source of lipids.

    “This suggests that exosomes can not only replenish TCA cycle metabolites but also act as source of lipids.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Metabolic reprogramming induced by stromal exosomes in cancer cells is not only Kras independent but is broadly observed in many cancers.

    “thus suggesting that metabolic reprogramming induced by stromal exosomes in cancer cells is not only Kras independent but is broadly observed in many cancers.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Exosomes carry a complex cargo that includes proteins, lipids, and miRNAs.

    “Exosomes are known to carry a complex cargo that includes proteins, lipids, and miRNAs (Costa-Silva et al., 2015; Simons and Raposo, 2009).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Costa-Silva et al., 2015 source

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    • cites Simons and Raposo, 2009

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    Premisecitation

    Paracrine signals from cancer cells can recruit and activate CAFs within the TME.

    “Accumulating evidence suggests that paracrine signals from cancer cells can both recruit and activate CAFs within the TME, and contribute to their activation (Whiteside, 2008; Liao et al., 2009; Orimo et al., 2005; Chung et al., 2006).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Whiteside, 2008 source

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    • cites Liao et al., 2009 source

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    Premisecitation

    Macropinocytosis of circulating proteins (especially albumin) can supply amino acids to nutrient-deprived cancer cells.

    “Recent studies have shown that macropinocytosis of circulating proteins (especially albumin) could supply amino acids to nutrient-deprived cancer cells (Commisso et al., 2013).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Commisso et al., 2013 source

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  • May combine two claims.

    Interpretationown data

    CDEs disable normal oxidative mitochondrial function in pancreatic cancer, and this regulation is similar in both wild-type and activated Kras expressing cells.

    “These results suggest that CDEs’ action of disabling normal oxidative mitochondrial function is exhibited also in pancreatic cancer and that this regulation is similar in both wild-type (BxPC3) and activated Kras (MiaPaCa-2) expressing cells.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Mitochondrial dysfunction can impair oxidative phosphorylation, the TCA cycle, fatty acid oxidation, the urea cycle, gluconeogenesis, and apoptotic pathways.

    “Mitochondrial dysfunction could impair oxidative phosphorylation, the TCA cycle, fatty acid oxidation, the urea cycle, gluconeogenesis, and apoptotic pathways (King et al., 2006; Modica-Napolitano and Singh, 2004).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites King et al., 2006 source

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    • cites Modica-Napolitano and Singh, 2004

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  • May combine two claims.

    Interpretationreasoning

    Exosomes may act as a source of metabolites and proliferating cancer cells use these metabolites for lipogenesis.

    “Results from the previous sections indicate that exosomes may act as a source of metabolites and proliferating cancer cells use these metabolites for lipogenesis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The increased ratio of α-ketoglutarate to citrate promotes reductive glutamine metabolism and correlates with reductive glutamine's contribution to citrate.

    “The increased ratio of α-ketoglutarate to citrate was recently shown to promote reductive glutamine metabolism and it correlated with reductive glutamine’s contribution to citrate (Fendt et al., 2013).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Fendt et al., 2013 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    CAFs can induce metabolic reprogramming in cancer cells.

    “Although it has been shown that CAFs can induce metabolic reprogramming in cancer cells (Brauer et al., 2013)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Brauer et al., 2013 source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductcitation

    In the proliferation, metabolic and tracer experiments, the ratio of CAFs to cancer cells was maintained between 1 and 5, and this ratio is physiologically relevant.

    “For the different types of experiments conducted herein (proliferation assays, metabolic assays and tracer experiments), this ratio was maintained between 1 and 5 CAFs per cancer cell, and hence is physiologically relevant.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Reductive carboxylation is a critical pathway to support the growth of tumor cells under hypoxia.

    “Previous reports showed that reductive carboxylation is a critical pathway to support the growth of tumor cells under hypoxia (Metallo, 2012; Mullen, 2012).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Metallo, 2012 source

      Not checked in the free run.

    • cites Mullen, 2012 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    All OCR or ECAR values were normalized to the protein content of the cells.

    “All OCR or ECAR value was normalized with protein content of cells.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Pyruvate is converted to acetyl-CoA through mitochondrial pyruvate dehydrogenase (PDH), whereas acetate is transported into cells and converted to acetyl-CoA through acetyl-CoA synthase.

    “Pyruvate is converted to acetyl-CoA through mitochondrial pyruvate dehydrogenase (PDH), whereas acetate is transported into cells and converted to acetyl-CoA through acetyl-CoA synthase (De Schrijver et al., 2003; Feron, 2009; Koukourakis et al., 2005; Pizer et al., 1996; Yoshimoto et al., 2001; Zaidi et al., 2012).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites De Schrijver et al., 2003

      Not checked in the free run.

    • cites Feron, 2009 source

      Not checked in the free run.

    • cites Koukourakis et al., 2005 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    The number of CAFs required to secrete the amount of exosomes that the cancer cells are exposed to should reflect the ratio of CAFs to cancer cells in tumor.

    “Hence, the number of CAFs required to secrete the amount of exosomes that the cancer cells are exposed to should reflect the ratio of CAFs to cancer cells in tumor.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Exosome-depleted FBS was used for cell culture when metabolic analysis or proliferation rate measurements were performed.

    “Exosome-depleted FBS (Systems Biosciences, Palo Alto, CA) was used for cell culture when metabolic analysis or proliferation rate measurements were performed.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Pyruvate or acetate can act as an alternative source to glucose and glutamine for lipid biosynthesis.

    “pyruvate or acetate can act as an alternative source to glucose and glutamine for lipid biosynthesis.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites De Schrijver et al., 2003

      Not checked in the free run.

    • cites Feron, 2009 source

      Not checked in the free run.

    • cites Koukourakis et al., 2005 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Study design and conductnone given

    It is extremely difficult to insert multiple miRNAs in exosomes or transfect multiple miRNAs together without causing significant toxicity due to limitations in genome engineering technologies.

    “due to limitations in genome engineering technologies, it is extremely difficult to insert multiple miRNAs in exosomes or transfect multiple miRNAs together without causing significant toxicity.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    PC3, DU145, 22RV1, BxPC3 and MiaPaCa-2 cell lines were authenticated by STR profiling against online ATCC profiles.

    “PC3, DU145, 22RV1, BxPC3 and MiaPaCa-2 were received from ATCC and authenticated by STR profiling with online ATCC profile.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Protein assays were used for normalization in the experiments.

    “Protein assays are used to do normalization in our experiment and is done according to Bicinchoninic Acid Protein Assay (Thermo Fisher Scientific, Waltham, MA) protocol.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    TME can supply metabolites directly to cancer cells through exosomes, and these metabolites can fuel TCA cycle in cancer cells.

    “These results conclusively showed that TME can supply metabolites directly to cancer cells through exosomes and these metabolites indeed can fuel TCA cycle in cancer cells.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    CDEs create hypoxia-mimicking environment in cancer cells, leading to increased reductive carboxylation of glutamine.

    “This suggests that CDEs create hypoxia mimicking environment in cancer cells leading to an increase in reductive carboxylation of glutamine in cancer cells.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: In reductive carboxylation, glutamine is converted to α-ketoglutarate, followed by conversion of α-ketoglutarate to isocitrate through isocitrate dehydrogenase (IDH), and isocitrate is converted to acetyl-CoA used for lipid synthesis.

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    To isolate exosomes, cells were cultured with exosome-depleted serum.

    “To isolate exosomes, cells were cultured with exosome-depleted serum.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Real-time PCR reactions for COX-1 and CYTB were normalized against GAPDH.

    “All reactions with COX-1 and CYTB were normalized against glyceraldehyde-3-phosphate dehydrogenase (GAPDH).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Patient-derived fibroblast cells had internal STR profiling maintained and checked annually.

    “Patient derived fibroblast cells were kindly provided by Drs. Donna Peehl and Anirban Maitra of Stanford University and MD Anderson, respectively and internal STR profiling is maintained and checked annually.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    The utilization of exosomes in cancer cell cultures was based on an exosome concentration of 100-400 μg/ml reported in the literature.

    “The utilization of exosomes in cancer cell cultures were based on application of 100–400 μg/ml of exosomes concentration that has been reported in literature (Christianson et al., 2013; Zhu et al., 2012).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Christianson et al., 2013 source

      Not checked in the free run.

    • cites Zhu et al., 2012 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Ultracentrifugation was used to remove possible exosomes from the FBS in the 13C-labeled RPMI medium.

    “ultracentrifugation was used to remove possible exosomes in FBS of this medium”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    A working concentration of 200 μg/ml was chosen for most experiments to maintain a physiological ratio of CAFs to cancer cells.

    “A working concentration of 200 μg/ml was chosen for most of the experiments in this study to maintain a physiological ratio of CAFs to cancer cells which is reported to be between 1–10 (Brauer et al., 2013; Hu et al., 2015; Delinassios, 1987).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Brauer et al., 2013 source

      Not checked in the free run.

    • cites Hu et al., 2015

      Not checked in the free run.

    • cites Delinassios, 1987

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing).

    Premisecitation

    Exosomes precondition specific organs for metastatic invasion.

    “Recently published article by Lyden et al (Hoshino et al., 2015), showed that exosomes precondition specific organs for metastatic invasion.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Hoshino et al., 2015 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    miRNA expression data were corrected for loading using the relative geometric means of endogenous miRNA levels as a correction factor.

    “The data were corrected for loading using the relative geometric means of endogenous miRNA levels as a correction factor.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductreasoning

    Fresh exosomes were used and freeze-thaw cycles avoided to minimize degradation of metabolites in exosomes.

    “to minimize degradation of metabolites in exosomes, we used fresh exosomes for all the experiments and avoided any freeze-thaw cycle in exosomes that were introduced to cancer cells cultures.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    All cell lines used were mycoplasma free based on PCR-based assays run every three months in the lab.

    “All cell lines were mycoplasma free based on PCR based assays run every three months in the lab.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductreasoning

    A concentration of 200 μg/ml exosome corresponds to a ratio between 1 and 5 CAFs per cancer cell, within the reported range.

    “A concentration of 200 μg/ml corresponded to ratio between 1 and 5 CAFs per cancer cell and hence, is within the range reported in the literature.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Degradation of metabolites can occur due to protracted purification steps during exosome isolation.

    “due to protracted purification steps during exosome isolation, degradation of metabolites can occur”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Upregulation of the reductive carboxylation pathway enhances cancer cell proliferation.

    “The upregulation of the reductive carboxylation pathway enhances cancer cells proliferation (Metallo, 2012; Mullen, 2012; Wise et al., 2011).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Metallo, 2012 source

      Not checked in the free run.

    • cites Mullen, 2012 source

      Not checked in the free run.

    • cites Wise et al., 2011 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Some tumors predominantly use glutamine under hypoxia or conditions mimicking hypoxia such as electron transport chain inhibition through reductive carboxylation for biosynthetic needs.

    “recent studies show that some tumors predominantly use glutamine under hypoxia or conditions mimicking hypoxia such as electron transport chain inhibition through reductive carboxylation for biosynthetic needs (Yang et al., 2014; Wise et al., 2008).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Yang et al., 2014 source

      Not checked in the free run.

    • cites Wise et al., 2008 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    TME is implicated in induced metabolic rewiring in cancer cells.

    “Recent findings implicate TME in the induced metabolic rewiring in cancer cells (Cairns et al., 2011; Fiaschi and Chiarugi, 2012; Rattigan et al., 2012).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Cairns et al., 2011 source

      Not checked in the free run.

    • cites Fiaschi and Chiarugi, 2012

      Not checked in the free run.

    • cites Rattigan et al., 2012 source

      Not checked in the free run.

79 of 79

  • The paper relies on this without support.

    The contribution of CDEs to CAF-induced metabolic reprogramming in cancer cells has not been elucidated.

    “Although it has been shown that CAFs can induce metabolic reprogramming in cancer cells (Brauer et al., 2013), the contribution of CDEs in this phenomenon, if any, has not been elucidated.”
    “little is known about CAF-derived exosomes (CDEs) and their metabolic influence on cancer cells.”

  • The paper relies on this without support.

    M1 pyruvate is only produced by glucose-6-phosphate metabolized by phospho glucoisomerase.

    “M1 pyruvate is only produced by glucose-6-phosphate metabolized by phospho glucoisomerase.”

  • The paper relies on this without support.

    Isotope tracer analysis can reveal alterations in contributions of a substrate within a particular metabolic pathway.

    “It is well established that isotope tracer analysis can reveal the alterations in contributions of a substrate within a particular metabolic pathway (Figure 3E).”

  • The paper relies on this without support.

    Proliferating cells under normoxia and hypoxia can utilize glutamine by oxidative metabolism and produce pyruvate through malic enzyme and further combine oxaloacetate with acetyl-CoA to form M4 citrate.

    “Proliferating cells under both normoxia and hypoxia can utilize glutamine by oxidative metabolism and produce pyruvate through malic enzyme and further combine oxaloacetate with acetyl-CoA to form M4 citrate (obtained by condensing of labeled oxaloacetate obtained from glutamine and unlabeled acetyl CoA).”

  • The paper relies on this without support.

    M5 citrate is further catalyzed to M3 fumarate and M3 malate in reductive glutamine metabolism.

    “M5 citrate is further catalyzed to M3 fumarate and M3 malate in this reductive glutamine metabolism.”

  • The paper relies on this without support.

    There is sparse data on the role of CAFs in altered cancer cell metabolism and the channels of communication that enable such paracrine effects.

    “However, there continues to be sparse data vis-à-vis the role, if any, of the effects CAFs might have on altered cancer cell metabolism, and the channels of communication that enable such paracrine effects.”

  • The paper relies on this without support.

    The role of exosomes in the metabolic crosstalk between cancer cells and TME is still unknown.

    “However, role of exosomes in the metabolic crosstalk between cancer cells and TME is still unknown.”

  • The paper relies on this without support.

    In reductive carboxylation, glutamine is converted to α-ketoglutarate, followed by conversion of α-ketoglutarate to isocitrate through isocitrate dehydrogenase (IDH), and isocitrate is converted to acetyl-CoA used for lipid synthesis.

    “In reductive carboxylation, glutamine is converted to α-ketoglutarate, followed by the conversion of α-ketoglutarate to isocitrate through isocitrate dehydrogenase (IDH), and isocitrate is converted to acetyl-CoA used for lipid synthesis.”

  • The paper relies on this without support.

    Acetyl-CoA is the first step in lipid biosynthesis, which serves biosynthetic needs of proliferating cells.

    “Acetyl-CoA is the first step in lipid biosynthesis, which serves biosynthetic needs of proliferating cells.”
9 of 9

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Exchange of metabolites such as pyruvate can be used by PDAC cells to maintain redox balance.

    “the exchange of metabolites such as pyruvate can be used by PDAC cells to maintain redox balance250.”

    From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [250]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • CytoD is reported to both inhibit and increase ECAR

    Major

    The results text says CytoD partially inhibited the exosome-induced increase in ECAR, while the caption for the same experiment says CytoD increased ECAR. This reverses the stated direction of an effect used to support the role of exosome uptake.

  • Figure 3A uses three versus six patient-derived CAF sources

    Minor

    The results text says Figure 3A used exosomes from three independent patient CAFs, whereas the figure caption specifies six.

  • Identity of a transfected miRNA differs between Results and Discussion

    Minor

    The Results identify miR-125b as one of the three co-transfected miRNAs in the Figure 2K experiment, but the Discussion identifies miR-25b instead.

  • Figure 2C uses three versus six patient-derived CAF sources

    Minor

    The results text attributes Figure 2C to exosomes from three independent patient CAFs, but its caption says six patient-derived CAFs were used.

4 of 4

Cites

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Related

Authors
Zhao, H., Yang, L., Baddour, J., Achreja, A., Bernard, V., Moss, T., Marini, J. C., Tudawe, T., Seviour, E. G., San Lucas, F. A., Alvarez, H., Gupta, S., Maiti, S. N., Cooper, L., Peehl, D., Ram, P. T., Maitra, A., & Nagrath, D.
Affiliations
  • Rice University (US)
  • The University of Texas MD Anderson Cancer Center (US)
  • The University of Texas System (US)
  • Baylor College of Medicine (US)
  • Departments of Pathology and Translational Molecular Pathology, Ahmad Center for Pancreatic Cancer Research, University of Texas MD Anderson Cancer Center, Houston, United States
  • Stanford Medicine (US)
Corresponding author
Nagrath, Deepak
ORCID
Venue
eLife
Publisher
eLife Sciences Publications, Ltd
Published
2016-02-27
Volume
5
Pages
e10250-e10250
ISSN
2050-084X (ISSN-L)
DOI
10.7554/elife.10250
PMC
PMC4841778
OpenAlex
W2274058631
Semantic Scholar
64d343d0a9dabf89df6c2d683e688d49d56fc9ef
Cited by
927
References
60
Citations by year
2026: 42 · 2025: 68 · 2024: 98 · 2023: 83 · 2022: 104 · 2021: 153 · 2020: 122 · 2019: 82 · 2018: 81 · 2017: 62 · 2016: 32
FWCI
44.54
Type
journal article
Language
en
Open access
Licence
Locations
  • eLife (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Rice Research Repository (Rice University) (submittedVersion, cc-by)
  • Rice Research Repository (Rice University) (submittedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
Keywords
exosomes, cancer-associated fibroblasts, tumor microenvironment, cancer metabolism, mitochondrial oxidative phosphorylation, glycolysis, amino acid supply, macropinocytosis, nutrient deprivation, TCA cycle intermediates, KRAS signaling, tumor growth
MeSH terms
Fermentation, Fibroblasts, Glucose, Glycolysis, Neoplasms, Oxidative Phosphorylation, Lactic Acid, Exosomes, Tumor Microenvironment

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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