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Cited by 11Cancer, Hypoxia, and MetabolismPancreatic and Hepatic Oncology ResearchCytokine Signaling Pathways and Interactions

Dynamic IL-6R/STAT3 signaling leads to heterogeneity of metabolic phenotype in pancreatic ductal adenocarcinoma cells

Open access
Blaszczak, Wiktoria, White, Bobby, Monterisi, Stefania, Swietach, Pawel·2024·Cell Reports
DOI 10.1016/j.celrep.2023.113612PMC PMC11149489
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Abstract

Malignancy is enabled by pro-growth mutations and adequate energy provision. However, global metabolic activation would be self-terminating if it depleted tumor resources. Cancer cells could avoid this by rationing resources, e.g., dynamically switching between "baseline" and "activated" metabolic states. Using single-cell metabolic phenotyping of pancreatic ductal adenocarcinoma cells, we identify MIA-PaCa-2 as having broad heterogeneity of fermentative metabolism. Sorting by a readout of lactic acid permeability separates cells by fermentative and respiratory rates. Contrasting phenotypes persist for 4 days and are unrelated to cell cycling or glycolytic/respiratory gene expression; however, transcriptomics links metabolically active cells with interleukin-6 receptor (IL-6R)-STAT3 signaling. We verify this by IL-6R/STAT3 knockdowns and sorting by IL-6R status. IL-6R/STAT3 activates fermentation and transcription of its inhibitor, SOCS3, resulting in delayed negative feedback that underpins transitions between metabolic states. Among cells manifesting wide metabolic heterogeneity, dynamic IL-6R/STAT3 signaling may allow cell cohorts to take turns in progressing energy-intense processes without depleting shared resources.

AI snapshot

Written from the paper’s full text.

TL;DR

Single-cell metabolic phenotyping of pancreatic ductal adenocarcinoma (PDAC) lines identifies MIA PaCa-2 as having broad heterogeneity in fermentative metabolism, separable by lactic acid permeability (PHLac). The study links this dynamic heterogeneity to IL-6R/STAT3 signaling and SOCS3-mediated delayed negative feedback, producing short-lived metabolic contrasts rather than hardwired sub-populations.

Key findings

  • PHLac-sorted MIA PaCa-2 sub-populations showed 3-fold higher fermentative and 4-fold higher respiratory rates in PHLachigh cells after 24 h, but the metabolic contrast decayed with a time constant of ∼30 h and collapsed by day 4.
  • PHLachigh cells grew 4-fold faster than PHLaclow cells over 4 days, yet both sub-populations returned symmetrically toward a mid-point metabolic phenotype, arguing against a heritable growth advantage.
  • RNA-seq identified 2,156 genes enriched in PHLachigh and 1,510 in PHLaclow cells; canonical glycolysis/gluconeogenesis and oxidative phosphorylation were not enriched (p.adj = 0.79 for both), while IL-6R/STAT3 signaling was prominently upregulated in PHLachigh cells.
  • IL-6R or STAT3 knockdown and STAT3 inhibition reduced fermentative rate; SOCS3 knockdown increased STAT3 phosphorylation and accelerated fermentative/respiratory rates, and SOCS3 knockout produced a major acid shift upon MCT inhibition (paired t test p = 0.0072), supporting delayed negative feedback.

Methods

  • Single-cell fluorimetric assays measured intracellular pH with cSNARF1 and rapid microperfusion switching to 2 mM CHC to block monocarboxylate transporters, yielding fermentative rate; PHLac was measured from pHi responses to lactate-containing versus lactate-free microstreams.
  • FACS-compatible sorting used cSNARF1-loaded cells equilibrated with 60 mM lactate then transferred to lactate-free medium; sub-populations were phenotyped by real-time medium acidification and O2 consumption, RNA-seq, RT-qPCR, immunoblotting, siRNA knockdown, CRISPR/Cas9 SOCS3 knockout, immunofluorescence, and MIA PaCa-2 xenografts in nude mice.
  • RNA-seq was performed on four independent sorts with DESeq2, clusterProfiler, and Ingenuity Pathway Analysis; metabolic and growth assays used plate-based fluorimetry and sulforhodamine B, with statistics by t tests or ANOVA as described.

Limitations

  • The paper states that FACS yield was low because of the short sorting window, limiting material for metabolomics or proteomics; major transcriptional differences between sub-populations may involve pathways other than IL-6R/STAT3/SOCS3; the mechanism was studied in MIA PaCa-2 and may not apply to other cancer cells; and experiments used 2D monolayers, omitting tumor microenvironment gradients.
  • The paper also states that in vivo benefit of dynamic metabolic heterogeneity remains to be demonstrated experimentally.
  • Evident from the text: the study is limited to PDAC cell lines and one xenograft model, so clinical or primary-tumor relevance is not established; the causal role of other DEGs and post-translational mechanisms is not fully dissected.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.celrep.2023.113612

Cites

56 of 56 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

37 of 47 cited sources checked · 10 supported · 1 flagged · accuracy not yet measured

  • Interpretationown data

    The faster growth of the metabolically activated sub-population suggests that a conducive metabolic state drives cell division rather than cell-cycle progression driving metabolic responses.

    “suggesting that a conducive metabolic state drives cell division rather than vice versa (cell-cycle progression driving metabolic responses8)”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [8] Takhaveev, 2023, Temporal segregation of biosynthetic processes is responsible for metabolic oscillations during the budding yeast cell cycle, Nat. Metab. source

      The citation is attached to the parenthetical claim that cell-cycle progression drives metabolic responses, not to the citing authors’ conclusion about faster-growing cells. In the Discussion (page unavailable), the source says biosynthetic and metabolic oscillations are ‘at least not primarily’ generated by cell-cycle activity; it instead links changes in primary metabolism to changing biosynthetic demands. (LLM, conf=0.88)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
  • Interpretationreasoning

    STAT3 activation potentiates IL-6 signaling by increasing receptor and ligand levels.

    “STAT3 activation potentiates IL-6 signaling by increasing receptor and ligand levels”
    Quote in the paperSubstantial claim4 of 4 sources checked
    • cites [35] Zhang, 2020, An integrative ENCODE resource for cancer genomics, Nat. Commun. source

      The Results section on regulatory networks discusses MYC and SUB1 regulation, not STAT3 activation or IL-6 signaling. Searches for STAT3, IL-6, and receptor and ligand levels found no passage in our copy addressing the claimed mechanism. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
    • cites [36] Moore, 2020, A curated benchmark of enhancer-gene interactions for evaluating enhancer-target gene prediction methods, Genome Biol. source

      The Results section discusses enhancer–gene interaction datasets and gene expression, not IL-6 signaling. Searches for STAT3 activation and for STAT3, IL-6, receptor, and ligand returned no passage addressing the claimed mechanism. (LLM, conf=0.75)

      Experimental — accuracy not yet measured
    • cites [37] Wang, 2013, STAT3 activation in response to IL-6 is prolonged by the binding of IL-6 receptor to EGF receptor, Proc. Natl. Acad. Sci. USA source

      The Discussion (page not provided) describes IL-6-driven secretion of more IL-6 and a second wave of STAT3 activation, supporting a feedback effect on ligand availability. It describes association of IL-6R with EGFR, not an increase in receptor levels caused by STAT3 activation. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [38] Huang, 2010, Signal transducer and activator of transcription 3 activation up-regulates interleukin-6 autocrine production: a biochemical and genetic study of established cancer cell lines and clinical isolated human cancer cells, Mol. Cancer source

      The Discussion (page unavailable) reports that STAT3 contributes to IL-6 autocrine production in the cancer cells tested, supporting increased ligand production. The Background identifies the IL-6 receptor subunits gp80 and gp130, but the cited passages do not show that STAT3 increases receptor levels. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
  • Study design and conductcitation

    The rate of intracellular acidification upon rapid MCT inhibition is a single-cell readout of fermentative rate.

    “Consequently, the rate of intracellular acidification is a single-cell readout of fermentative rate.22”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [22] Blaszczak, 2022, Autoregulation of H(+)/lactate efflux prevents monocarboxylate transport (MCT) inhibitors from reducing glycolytic lactic acid production, Br. J. Cancer source
  • Premisecitation

    IL-6R evokes a myriad of responses, including metabolic actions, through STAT3.

    “IL-6R evokes a myriad of responses, including metabolic actions, through STAT3.31,32,33,34”
    Quote in the paperSubstantial claim4 of 4 sources checked
    • cites [31] Bollrath, 2009, gp130-mediated Stat3 activation in enterocytes regulates cell survival and cell-cycle progression during colitis-associated tumorigenesis, Cancer Cell source

      The Significance section explains that IL-6 receptor signaling through gp130 engages STAT3, and the Discussion describes effects on cell survival and proliferation. The passages do not describe metabolic actions, so that specific part of the claim is unsupported by our copy. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [32] Cronin, 2016, Signal transducer and activator of transcription-3 licenses Toll-like receptor 4-dependent interleukin (IL)-6 and IL-8 production via IL-6 receptor-positive feedback in endometrial cells, Mucosal Immunol. source

      The Introduction states that IL-6 activates STAT3 through the IL-6 receptor, and the Discussion says IL6R activation changes target-gene expression via STAT3. Neither passage supports the claimed metabolic actions; the paper discusses inflammatory responses in endometrial cells. Page numbers are unavailable in our copy. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [33] Grivennikov, 2009, IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer, Cancer Cell source

      The Discussion (page unavailable) says IL-6 binding to its gp130-associated receptor activates the JAK1/2–STAT3 pathway and identifies STAT3 as a critical effector in colitis-associated cancer. It discusses effects on intestinal epithelial cell survival and proliferation, but does not establish the claimed metabolic actions through STAT3. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [34] Teoh, 2020, IL6R-STAT3-ADAR1 (P150) interplay promotes oncogenicity in multiple myeloma with 1q21 amplification, Haematologica source

      The Introduction (page not provided) describes IL-6 binding to IL6R and activating STAT3, while the Discussion reports resulting growth and proliferation in myeloma cells. Neither passage identifies metabolic actions as one of the responses, so that part of the claim is unsupported by our copy. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
  • Findingown data

    Supplementation with IL-6 or hyIL-6 prior to metabolic phenotyping has no added effect in MIA PaCa-2 cells.

    “supplementation with IL-6 or its synthetic fusion protein, hyper-IL-6 (hyIL-6), 24 prior to metabolic phenotyping had no added effect”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [24] Blaszczak, 2021, Cost-Effective Real-Time Metabolic Profiling of Cancer Cell Lines for Plate-Based Assays, Chemosensors source

      Section 3.4.3 describes metabolic measurements in MIA-PaCa-2 cells after changing the substrate or adding rotenone. The Appendix figure captions likewise describe substrate and rotenone experiments, but neither these passages nor searches for IL-6 and hyIL-6 address cytokine supplementation or whether it had no added effect. No page number is provided in our copy for these passages. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
  • Classified as probably not a substantial claim. 41
  • May combine two claims. 28
  • The quote only partly states this claim. 2

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

    Premisecitation

    KRAS mutations lead to sustained activation of MAPK and PI3K-mTOR pathways.

    “KRAS mutations lead to sustained activation of MAPK and PI3K-mTOR pathways16,17”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [16] Ying, 2012, Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism, Cell source
    • cites [17] Santana-Codina, 2018, Oncogenic KRAS supports pancreatic cancer through regulation of nucleotide synthesis, Nat. Commun. source

      The Results section, “The MAPK-MYC-RPIA pathway mediates KRAS resistance” (page unavailable), supports KRAS-dependent MAPK signaling: KRAS depletion decreased ERK phosphorylation. It does not establish sustained PI3K-mTOR activation by KRAS mutations; it reports only a minor effect of KRAS depletion on AKT and describes PI3K activation as a compensatory response to MEK inhibition. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

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

    Premisecitation

    Single-cell methods applied to cancer cells have described heterogeneity in transcriptomics, epigenomics, metabolomics, and proteomics.

    “Indeed, single-cell methods applied to cancer cells have described heterogeneity in terms of transcriptomics, epigenomics, metabolomics, and proteomics,5,6”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [5] Dagogo-Jack, 2018, Tumour heterogeneity and resistance to cancer therapies, Nat. Rev. Clin. Oncol. source
    • cites [6] Lawson, 2018, Tumour heterogeneity and metastasis at single-cell resolution, Nat. Cell Biol. source

      The review describes transcriptomic, epigenetic and proteomic differences between cancer cells (opening section, page unavailable), and its diagnostics section reports heterogeneity detected by single-cell RNA-seq and mass cytometry. It does not describe single-cell metabolomic heterogeneity in cancer cells; searches for “metabolomics” and “metabolite” found no supporting passage. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation

    Bulk fermentative and respiratory rates in primary tumors are lower than previously postulated.

    “Intriguingly, a recent study determined that “bulk” fermentative and respiratory rates in primary tumors are lower than previously postulated,4”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [4] Bartman, 2023, Slow TCA flux and ATP production in primary solid tumours but not metastases, Nature source

      The Abstract and Discussion report suppressed TCA flux in primary solid tumour models and lower overall ATP production than the commonly assumed hypermetabolic state. But ‘Tumours make energy slowly’ reports glycolytic flux similar to or higher than that of corresponding healthy tissues; the paper does not establish that fermentative rates are lower than previously postulated. The findings concern the primary tumour models studied, not primary tumours generally. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

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

    Premisecitation

    The cell cycle is an example of a rhythmic signaling cascade, but coupling metabolism to it would constrain metabolic activation to specific stages of the cell cycle.

    “One example is the cell cycle,8 but this arrangement would constrain metabolic activation to specific stages of the cell cycle, which may not necessarily deliver the best matching between metabolic demand and supply, particularly during longer phases of the cycle.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [8] Takhaveev, 2023, Temporal segregation of biosynthetic processes is responsible for metabolic oscillations during the budding yeast cell cycle, Nat. Metab. source

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

    Premisecitation

    TP53 mutations disinhibit glucose metabolism.

    “mutations in TP53 disinhibit glucose metabolism.18,19”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [18] Zhang, 2013, Tumour-associated mutant p53 drives the Warburg effect, Nat. Commun. source
    • cites [19] Kondoh, 2005, Glycolytic enzymes can modulate cellular life span, Cancer Res. source

      In “Immortalization Correlates with Effects on Glycolysis” (page not available), mouse embryonic fibroblasts expressing dominant-negative p53 showed increased glucose detritiation and lactate production, while induced wild-type p53 reduced PGM activity. This supports the direction of the claim, but the experiments do not establish that TP53 mutations generally disinhibit glucose metabolism. (LLM, conf=0.83)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Proliferation is costly in terms of energy and substrates, and maintaining a persistently raised metabolic rate would be counter-productive if it caused the tumor to become depleted of resources and overloaded with waste.

    “However, proliferation is costly in terms of energy and substrates, and maintaining a persistently raised metabolic rate would be counter-productive if it caused the tumor to become depleted of resources and overloaded with waste.3”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [3] Kamphorst, 2015, Human pancreatic cancer tumors are nutrient poor and tumor cells actively scavenge extracellular protein, Cancer Res. source

      The Introduction says tumor growth has high metabolic demands and that poor perfusion may limit oxygen and nutrients. The Discussion describes PDAC tumors as nutrient-poor, but the paper does not say that a persistently raised metabolic rate would be counterproductive or that tumors become overloaded with waste. Page numbers are not available in our copy. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Pancreatic ductal adenocarcinoma (PDAC) lines were chosen because cancers of the pancreas are characterized by rapid progression, invasiveness, and elevated fermentative metabolism.

    “Pancreatic ductal adenocarcinoma (PDAC) lines were chosen for our study because cancers of the pancreas are characterized by rapid progression,9,10 invasiveness,11,12 and elevated fermentative metabolism.13,14,15,16”
    Quote in the paperSubstantial claim6 of 8 sources checked
    • cites [9] Nishida, 1999, Doubling time of serum CA 19-9 in the clinical course of patients with pancreatic cancer and its significant association with prognosis, J. Surg. Oncol. source
    • cites [10] Yu, 2015, Time to progression of pancreatic ductal adenocarcinoma from low-to-high tumour stages, Gut source
    • cites [11] Kleeff, 2016, Pancreatic cancer, Nat. Rev. Dis. Prim. source
    • cites [12] Nie, 2020, COX6B2 drives metabolic reprogramming toward oxidative phosphorylation to promote metastasis in pancreatic ductal cancer cells, Oncogenesis source

      The Introduction describes PDAC as highly aggressive, with patients often dying within months, and attributes its aggressiveness partly to high metastatic potential. It reports both Warburg and anti-Warburg metabolism in PDAC, however, so it does not support characterizing pancreatic cancers generally by elevated fermentative metabolism. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [13] Lunt, 2011, Aerobic glycolysis: meeting the metabolic requirements of cell proliferation, Annu. Rev. Cell Dev. Biol. source

      The Introduction (page unavailable) says cancer cells often consume more glucose and produce high levels of lactate, supporting the elevated fermentative-metabolism part of the sentence. It does not identify pancreatic cancer or PDAC lines specifically. The progression and invasiveness claims are attached to other citations. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
    • cites [14] Wang, 2022, Prognostic value of glycolysis markers in pancreatic cancer: A systematic review and meta-analysis, Front. Oncol. source
    • cites [15] Yang, 2020, The enhancement of glycolysis regulates pancreatic cancer metastasis, Cell. Mol. Life Sci. source
    • cites [16] Ying, 2012, Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism, Cell source

  • May combine two claims.

    Findingcitation

    Cx43 levels are low in MIA PaCa-2 primary tumors but increase in areas of invasion and metastasis.

    “we showed that Cx43 levels are low in MIA PaCa-2 primary tumors but increase in areas of invasion and metastasis”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [48] Dovmark, 2017, Connexin-43 channels are a pathway for discharging lactate from glycolytic pancreatic ductal adenocarcinoma cells, Oncogene source

      The Results section reports no Cx43 immunoreactivity in the MIA PaCa-2 primary tumor and markedly increased staining in invading cells. It also says Cx43 staining was weak or absent in most lung metastases, although some metastatic lesions were positive; the claim overgeneralizes the metastatic finding. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    pSTAT3 induces transcription of multiple genes, including IL6 and IL6R, which amplifies IL-6/STAT3 signaling.

    “pSTAT3 induces the transcription of multiple genes, including IL6 and IL6R, which has the effect of amplifying IL-6/STAT3 signaling.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [41] Chang, 2013, The IL-6/JAK/Stat3 feed-forward loop drives tumorigenesis and metastasis, Neoplasia source

      In “Stat3–IL-6 Feed-Forward Loop Regulates Mammary Tumorigenesis” (page not specified), the paper reports Stat3 binding to the IL-6 promoter and proposes a transcriptional feed-forward loop. The Discussion (page not specified) reports that disrupting Stat3 reduces IL-6 expression. The copy does not show that pStat3 induces IL6R transcription; it discusses IL-6R as a receptor in the signaling pathway. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Interpretationcitation

    Desynchronized dynamics would ration resources evenly, while maintaining a relatively normal bulk metabolic rate, as shown in primary tumors.

    “Desynchronized dynamics would ration resources evenly, while maintaining a relatively “normal” bulk metabolic rate, as shown in primary tumors.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [6] Lawson, 2018, Tumour heterogeneity and metastasis at single-cell resolution, Nat. Cell Biol. source

      The Non-genetic heterogeneity and cellular differentiation section (page unavailable) mentions differences in cellular metabolic state, but does not discuss desynchronized dynamics, even resource allocation, or a normal bulk metabolic rate in primary tumours. Searches for those terms and related concepts found no passage addressing the attributed claim. (LLM, conf=0.76)

      Experimental — accuracy not yet measured

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

    Premisecitation

    IL-6Rα expression is normally associated with hepatocytes and leukocytes but has also been described in cancer cells, including PDAC.

    “IL-6Rα expression is normally associated with hepatocytes and leukocytes but has also been described in cancer cells, including PDAC.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [40] Heinrich, 2003, Principles of interleukin (IL)-6-type cytokine signalling and its regulation, Biochem. J. source

      The Introduction (page not available in our copy) says α-receptor expression is more restricted than gp130 expression, supporting the claim’s general point about limited distribution. It does not identify hepatocytes and leukocytes as the usual IL-6Rα-expressing cells. The PI3K section discusses IL-6 signalling in several cancer cell types, but does not establish IL-6Rα expression in those cells or mention PDAC. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation

    The cytokine IL-6 triggers multiple downstream responses, including metabolic regulation.

    “The cytokine IL-6 triggers multiple downstream responses, including metabolic regulation.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [40] Heinrich, 2003, Principles of interleukin (IL)-6-type cytokine signalling and its regulation, Biochem. J. source

      The Introduction (page not provided) describes multiple IL-6-type cytokine responses and signalling pathways, and the PI3K section specifically discusses effects of IL-6. The passages do not establish metabolic regulation as one of those responses; a search for that term and for glucose metabolism found no supporting passage. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Pancreatic cancers generate substantial lactic acid fluxes, linked to mutations that promote hyper-proliferation.

    “pancreatic cancers generate substantial lactic acid fluxes, linked to mutations that promote hyper-proliferation”
    Quote in the paperSubstantial claim4 of 4 sources checked
    • cites [16] Ying, 2012, Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism, Cell source
    • cites [17] Santana-Codina, 2018, Oncogenic KRAS supports pancreatic cancer through regulation of nucleotide synthesis, Nat. Commun. source

      The Results section ('Kras dependency correlates with differential metabolic rewiring'; page unavailable) reports that KRAS depletion reduced glycolytic intermediates and extracellular acidification in human pancreatic cancer cell lines, supporting a link between an oncogenic mutation and altered metabolism. The Methods ('Metabolism studies'; page unavailable) describe measuring lactate production, but the retrieved passages do not establish that pancreatic cancers generate substantial lactic acid fluxes or directly link such fluxes to hyper-proliferation. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [18] Zhang, 2013, Tumour-associated mutant p53 drives the Warburg effect, Nat. Commun. source

      The Results section ('Mutp53 stimulates the Warburg Effect in vitro and in vivo'; page unavailable) reports increased lactate production in mutant-p53 lung and breast cancer cells and links mutant p53 to the Warburg effect. It does not establish substantial lactic acid fluxes in pancreatic cancers specifically, or show that those fluxes are linked to mutations promoting hyper-proliferation there. The only pancreatic-cancer mention found is in a reference title. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [19] Kondoh, 2005, Glycolytic enzymes can modulate cellular life span, Cancer Res. source

      The Introduction (page unavailable) links enhanced aerobic glycolysis in cancer with expression of oncogenes, and the ‘Immortalization Correlates with Effects on Glycolysis’ section reports increased lactate production relative to glucose consumption in engineered mouse cells. The paper does not establish substantial lactic acid flux specifically in pancreatic cancers or link that flux to mutations promoting hyper-proliferation. (LLM, conf=0.83)

      Experimental — accuracy not yet measured

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

    Premisecitation

    IL-6 signaling facilitates the progression of pre-neoplastic lesions to malignant forms, and negative feedback by SOCS3 proteins decreases primary tumor growth.

    “IL-6 signaling facilitates the progression of pre-neoplastic lesions to malignant forms, and negative feedback by SOCS3 proteins was found to decrease primary tumor growth.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [45] Lesina, 2011, Stat3/Socs3 activation by IL-6 transsignaling promotes progression of pancreatic intraepithelial neoplasia and development of pancreatic cancer, Cancer Cell source

      The Discussion (page unavailable) states that IL-6 transsignaling promotes progression of preneoplastic pancreatic lesions and development of pancreatic cancer. The Results (page unavailable) identify SOCS3 as a negative-feedback inhibitor and show that deleting it accelerates lesion progression and shortens tumor latency. The paper does not establish that SOCS3 feedback decreases the growth of an existing primary tumor. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingown data

    STAT3 knockdown ablated STAT3 expression and reduced fermentative rate.

    “Knockdown ablated STAT3 expression, and acute treatment with napabucasin (1 μM) reduced STAT3 phosphorylation; both reduced fermentative rate (Figures 4F, 4G, and S7A).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    IL6R, IL6ST, BAG4, EFNB2, and FOXJ1 were more highly expressed in PANC-1 compared to MIA PaCa-2 cells, consistent with the CCLE analyses.

    “Moreover, IL6R, IL6ST, BAG4, EFNB2, and FOXJ1 were more highly expressed in PANC-1 compared to MIA PaCa-2 cells, consistent with the CCLE analyses.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    BxPC-3 and HPAC cells had low STAT3 levels that were distributed uniformly between the nucleus and cytoplasm.

    “BxPC-3 and HPAC cells had low STAT3 levels that were distributed uniformly between the nucleus and cytoplasm.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The highest STAT3 signals were reported in PANC-1 and MIA PaCa-2 cells, of which MIA PaCa-2 also showed evidence for a broader distribution of the nuclear/cytoplasmic STAT3 ratio.

    “The highest STAT3 signals were reported in PANC-1 and MIA PaCa-2 cells, of which the latter also showed evidence for a broader distribution of the nuclear/cytoplasmic STAT3 ratio.”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    STAT3 inhibition with napabucasin decreases IL-6 production in MIA PaCa-2 cells.

    “STAT3 inhibition with napabucasin decreased IL-6 production”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    PHLachigh and PHLaclow sub-populations resolved well on principal-component analysis and showed distinct patterns of gene expression.

    “PHLachigh and PHLaclow sub-populations resolved well on principal-component analysis (Figure 3A) and showed distinct patterns of gene expression (Figure 3B; Table S2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Laconic detected a rise in [lactate] when superfusates were switched from galactose containing to lactate containing, but the response was modest and comparable to baseline variation.

    “Although Laconic detected a rise in [lactate] when superfusates were switched from galactose containing to lactate containing, the response was modest and comparable to baseline variation (Figure S1D).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The PHLac distribution was narrowest in HPAC and broadest in MIA PaCa-2, matching the distributions of fermentative rate.

    “The PHLac distribution was narrowest in HPAC and broadest in MIA PaCa-2 (Figure 1D), matching the distributions of fermentative rate (Figure 1B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    STAT3 levels were even lower in AsPC-1 and Colo-357 cells, with some degree of non-uniformity.

    “STAT3 levels were even lower in AsPC-1 and Colo-357 cells, with some degree of non-uniformity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Cells from the top and bottom deciles of the PHLac distribution produced lactate-evoked pHi transients of markedly different time courses, providing a window for flow-cytometric sorting using pHi-sensitive fluorescence.

    “Cells from the top and bottom deciles of the PHLac distribution produced lactate-evoked pHi transients of markedly different time courses, providing a window for flow-cytometric sorting using pHi-sensitive fluorescence (Figure 1E).”
    Quote in the paperSubstantial claim

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

    Findingown data

    There were major transcriptional differences between sub-populations of contrasting metabolic rates that may relate to pathways other than IL-6R/STAT3/SOCS3.

    “there were major transcriptional differences between sub-populations of contrasting metabolic rates that may relate to pathways other than IL-6R/STAT3/SOCS3”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisenone given

    The extent and causes of within-population metabolic heterogeneity in PDAC remain unclear.

    “However, the extent and causes of within-population metabolic heterogeneity remain unclear.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    IL-6R/STAT3 activates fermentation and transcription of its inhibitor SOCS3, resulting in delayed negative feedback that underpins transitions between metabolic states.

    “IL-6R/STAT3 activates fermentation and transcription of its inhibitor, SOCS3, resulting in delayed negative feedback that underpins transitions between metabolic states.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

    Premisereasoning

    One way of managing resources is through rationing, which could be implemented by alternating the metabolic activity of cells between low and high states, thereby establishing dynamic heterogeneity.

    “One way of managing resources is through rationing, which could be implemented by alternating the metabolic activity of cells between “low” and “high” states, thereby establishing dynamic heterogeneity.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Mutations enabling rapid proliferation are selected positively in cancers because they accelerate the emergence of aggressive phenotypes through somatic evolution.

    “Mutations enabling rapid proliferation are selected positively in cancers because they accelerate the emergence of aggressive phenotypes through somatic evolution.1,2”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [1] Gatenby, 2020, Integrating evolutionary dynamics into cancer therapy, Nat. Rev. Clin. Oncol. source
    • cites [2] Nowell, 1976, The clonal evolution of tumor cell populations, Science source

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given

    Genotypes with hard-wired metabolic activation may have an inherent growth advantage and could, with time, overtake the tumor.

    “genotypes with hard-wired metabolic activation may have an inherent growth advantage and could, with time, overtake the tumor.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisenone given

    Most observations of metabolic heterogeneity have been based on snapshots that describe heterogeneity at the point of measurement but cannot predict dynamics over time.

    “However, most observations have been based on “snapshots” that describe heterogeneity at the point of measurement but cannot predict dynamics over time.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based).

    Premisereasoning

    Such a system could be implemented by coupling metabolism onto signaling cascades that show rhythm.

    “Such a system could be implemented by coupling metabolism onto signaling cascades that show rhythm.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

    Premisenone given

    Metabolism is an ensemble process that depends on a network of proteins and their kinetic and thermodynamic constraints.

    “Since metabolism is an ensemble process that depends on a network of proteins and their kinetic and thermodynamic constraints, single-cell methods that measure gene expression may not adequately separate sub-populations by metabolic flux.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

    Premisereasoning

    A sustainable form of dynamic heterogeneity would require cells to seamlessly alternate between metabolic states.

    “A sustainable form of dynamic heterogeneity would require cells to seamlessly alternate between metabolic states.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    A simple cycling process requires delayed negative feedback.

    “A minimum requirement for a simple cycling process is to feature delayed negative feedback”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [20] Monk, 2003, Oscillatory expression of Hes1, p53, and NF-kappaB driven by transcriptional time delays, Curr. Biol. source

  • May combine two claims.

    Interpretationown data

    Phenotype may be shaped by the state of signaling and contributions from thermodynamic, allosteric, and post-translational factors that are not captured by transcriptomics.

    “Instead, phenotype may be shaped by the state of signaling and contributions from thermodynamic, allosteric, and post-translational factors that are not captured by transcriptomics.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    2-NBDG loading did not inhibit glycolysis.

    “NB: 2-NBDG loading did not inhibit glycolysis”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisereasoning

    Cells with high fermentation rates require adequate capacity to conduct an efflux of lactate across the membrane to match their glycolytic production.

    “We reasoned that cells with high fermentation rates require adequate capacity to conduct an efflux of lactate across the membrane to match their glycolytic production.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisereasoning

    Under the constraints of flux balance, cells with a higher glycolytic rate are expected to have greater capacity to remove lactic acid across the membrane.

    “Under the constraints of flux balance, cells with a higher glycolytic rate are expected to have greater capacity to remove lactic acid across the membrane.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    Selected DEGs were verified by RT-qPCR analysis of independently collected MIA PaCa-2 samples.

    “Selected DEGs were verified by RT-qPCR analysis of independently collected MIA PaCa-2 samples (Figure 3F).”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    A saturation phenomenon may limit the ability of PANC-1 cells to generate heterogeneity.

    “A saturation phenomenon may limit the ability of PANC-1 cells to generate heterogeneity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In other cell types, activated STAT3 induces SOCS3 expression, and SOCS3 inhibits JAKs responsible for phosphorylating STAT3.

    “activated STAT3 induces SOCS3 expression, the protein product of which inhibits Janus kinases (JAKs) responsible for phosphorylating STAT3”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [39] Brender, 2001, STAT3-mediated constitutive expression of SOCS-3 in cutaneous T-cell lymphoma, Blood source

  • Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.

    Premisenone given

    Glucose uptake is the first step in metabolism, but its relationship to metabolic flux is less intuitive.

    “Although glucose uptake is the first step in metabolism, its relationship to metabolic flux is less intuitive.”
    Quote in the paperNot a substantial claim

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

    Interpretationown data

    The transient stimulation of respiration upon STAT3 inhibition may be a compensatory response.

    “Strikingly, the effect of STAT3 inhibition on blocking fermentation transiently stimulated respiration, which may be a compensatory response (Figure S7B).”
    Quote in the paperNot a substantial claim

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

    Interpretationreasoning

    The mechanism described in MIA PaCa-2 cells can explain one aspect of metabolic heterogeneity in this PDAC line, but other mechanisms may be relevant in other cancer cells.

    “The mechanism described in MIA PaCa-2 cells can explain one aspect of metabolic heterogeneity in this PDAC line, but other mechanisms may be relevant in other cancer cells.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    The study's scope was limited by the low yield of cells obtained by FACS because of the short window for sorting.

    “The scope of our investigation was limited by the low yield of cells obtained by FACS because of the short window for sorting.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing). May combine two claims.

    Interpretationreasoning

    Other genes may contribute to the distinct phenotypes and warrant further testing.

    “other genes may contribute to the distinct phenotypes and warrant further testing”
    Quote in the paperNot a substantial claim

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

    Interpretationreasoning

    Metabolic rate may seamlessly alternate between states, giving cancer cells a time-window for engaging energetically-demanding processes, such as protein synthesis or cell division.

    “Metabolic rate may seamlessly alternate between states, giving cancer cells a time-window for engaging energetically-demanding processes, such as protein synthesis or cell division.”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Interpretationreasoning

    The IL-6R/STAT3/SOCS3 cascade drives metabolic heterogeneity.

    “A role of the IL-6R/STAT3/SOCS3 cascade in driving metabolic heterogeneity is novel”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    A delayed negative feedback circuit in IL-6R/STAT3/SOCS3 would cause the metabolism-activating effect of IL-6 to be rhythmic and produce dynamic metabolic heterogeneity at the population level.

    “Inherently, such a circuit would cause the metabolism-activating effect of IL-6 to be rhythmic, which—in turn—would produce dynamic metabolic heterogeneity observed at the population level.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    SOCS3 operates a delayed negative feedback, which is one mechanism for producing rhythmic activity.

    “SOCS3 operates a delayed negative feedback, which is one mechanism for producing rhythmic activity.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [20] Monk, 2003, Oscillatory expression of Hes1, p53, and NF-kappaB driven by transcriptional time delays, Curr. Biol. source

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

    Interpretationnone given

    2D monolayer growth could itself produce metabolic variation.

    “which could, per se, produce metabolic variation”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    The study was limited to measurements of cells grown as 2D monolayers.

    “this study was limited to measurements of cells grown as 2D monolayers”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    The expression of GAPDH and SNW1 were used for internal calibration.

    “The expression of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and SNW Domain Containing 1 (SNW1) were used for internal calibration.”
    Quote in the paperNot a substantial claim

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

    Interpretationnone given

    In tumors, an additional layer of metabolic heterogeneity will arise because of the immediate environment of cells, such as gradients of signaling molecules.

    “In tumors, an additional layer of metabolic heterogeneity will arise because of the immediate environment of cells, such as gradients of signaling molecules.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    All animal procedures followed the Animals (Scientific Procedures) Act 1986 and were authorized by Project License no. PPL P01A04016.

    “All animal procedures followed the Animals (Scientific Procedures) Act 1986 and were authorized by Project License no. PPL P01A04016.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    Prior to measurements, media were covered with a layer of 150 μL mineral oil to impose a barrier to gas diffusion.

    “Prior to measurements, media were covered with a layer of 150 μL mineral oil (M5904, Sigma) to impose a barrier to gas diffusion.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    β-actin protein was used as a loading control.

    “β-actin (1:5000, Proteintech, #HRP-60008) protein was used as a loading control.”
    Quote in the paperNot a substantial claim

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

    Study design and conductcitation

    The intracellular pH ratio was calibrated to units of pH using a calibration curve determined in separate experiments using the nigericin technique.

    “The ratio was calibrated to units of pH using a calibration curve determined in separate experiments using the nigericin technique.52”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [52] Dovmark, 2018, Normoxic cells remotely regulate the acid-base balance of cells at the hypoxic core of connexin-coupled tumor growths, Faseb. J. source

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

    Study design and conductnone given

    Cell lines authentication based on STR profiling was conducted in the AuthentiCell service provided by the European Collection of Authenticated Cell Cultures.

    “Cell lines authentication based on Short Tandem Repeat (STR) profiling was conducted in the AuthentiCell service provided by the European Collection of Authenticated Cell Cultures.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Study design and conductnone given

    Limiting the sorting period to 10 min adequately distinguishes cells with high and low MCT permeability (alkaline and acidic pHi).

    “The sorting period was limited to 10 min, which adequately distinguishes cells with high and low MCT permeability (alkaline and acidic pHi).”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    In flow cytometric sorting, dead, DAPI-stained cells and cell doublets were excluded from the gating.

    “The dead, DAPI-stained cells, and cell doublets were excluded from the gating.”
    • Also stated in: § Method details · plain
      “The dead, DAPI-stained cells, and cell doublets were excluded from the gating.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    SOCS3 knock-out was confirmed by Western blotting.

    “SOCS3 knock-out was confirmed by Western blotting.”
    Quote in the paperSubstantial claim
63 of 63

  • The paper relies on this without support.

    MIA PaCa-2 cells are a suitable model for studying metabolic heterogeneity in PDAC.

    “Among the PDAC lines, we identified MIA PaCa-2 as having the broadest metabolic heterogeneity and used these cells to validate our sorting strategy.”

  • The paper relies on this without support.

    The metabolic phenotype of MIA PaCa-2 cells in culture reflects the behavior of PDAC cells in tumors in vivo.

    “Next, we investigated the state of STAT3 signaling in MIA PaCa-2 xenografts.”

  • The paper relies on this without support.

    SOCS3 transcription and translation incur a time delay.

    “Since SOCS3 transcription and translation incur a time delay”

  • The paper relies on this without support.

    Glycolytic lactic acid production must be in balance with its transmembrane excretion.

    “glycolytic lactic acid production must be in balance with its transmembrane excretion”

  • The paper relies on this without support.

    Membrane permeability properties are less labile than metabolite concentrations and relate more directly to actual flux.

    “membrane permeability properties are less labile than metabolite concentrations and relate more directly to actual flux”

  • The paper relies on this without support.

    A point measurement cannot infer flux, and metabolite levels can be labile during sample preparation and sorting.

    “a point measurement cannot infer flux, and metabolite levels can be labile during sample preparation and sorting”

  • The paper relies on this without support.

    Upon forming the IL-6 receptor complex, JAKs phosphorylate gp130, triggering STAT3 phosphorylation to its active form.

    “Upon forming the receptor complex, JAKs phosphorylate gp130, triggering STAT3 phosphorylation to its active form.”
7 of 7

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.

  • Nearest-neighbor correlation method is reported as both Pearson and Spearman

    Minor

    The Figure 5 legend says the nearest-neighbor analysis used Pearson's correlation coefficient, while the methods say it used Spearman's coefficient for the same analysis.

  • Materials statement conflicts with paper-generated constructs

    Minor

    The materials availability statement says the study generated no unique reagents, but the key resources table identifies lentiCRISPR constructs made in this paper.

2 of 2

Cites

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Related

Authors
Blaszczak, W., White, B., Monterisi, S., & Swietach, P.
Affiliations
University of Oxford (GB)
Corresponding author
Swietach, Pawel
ORCID
Venue
Cell Reports
Publisher
Elsevier BV
Published
2024-01
Volume
43
Issue
1
Pages
113612
ISSN
2211-1247 (ISSN-L)
DOI
10.1016/j.celrep.2023.113612
PMC
PMC11149489
OpenAlex
W4390130159
Semantic Scholar
8cd8dd180e059af18e5d80e6b44ad6de8b050395
Cited by
9
References
56
Citations by year
2026: 3 · 2025: 2 · 2024: 4
FWCI
1.07
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Reports (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Cancer Research UK (100200)
  • European Research Council (723997)
  • Commission of the European Communities (813834)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
Keywords
pancreatic ductal adenocarcinoma, metabolic heterogeneity, fermentative metabolism, glycolysis, SOCS3, negative feedback, MIA PaCa-2 cells, tumor energy metabolism
MeSH terms
Humans, Pancreatic Neoplasms, Phenotype, Signal Transduction, Receptors, Interleukin-6, Carcinoma, Pancreatic Ductal, STAT3 Transcription Factor

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 2026-10-23.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-23.

Cited sources are checked by gpt-6-sol.

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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